CN114409674A - Synthetic method of JAK inhibitor Pacritinib - Google Patents
Synthetic method of JAK inhibitor Pacritinib Download PDFInfo
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Abstract
The invention relates to a synthesis method of a JAK inhibitor Pacritinib, which comprises the steps of carrying out etherification reaction on an intermediate E and trans-1, 4-dibromo-2-butene to obtain an intermediate 7, and reacting the intermediate 7 with pyrrolidine to obtain the Pacritinib; the invention carries out cyclization reaction through Williams etherification reaction with milder and simpler conditions, and the reaction can be carried out by stirring at room temperature, the reaction conditions are mild, noble metal catalysts are not needed, nitrogen gas is not needed for protection, the product has no cis-form configuration, the separation and purification are more convenient, and the reaction route is short.
Description
Technical Field
The invention relates to a synthesis method of a JAK inhibitor Pacritinib, belonging to the technical field of medicinal chemistry.
Background
Pacritiniib (SB1518), molecular formula: c28H32N4O3CAS registry number 937272-79-2, chemical name (16E) -11- [ (2-pyrrolidin-1-yl) ethoxy]-14, 19-dioxa-5, 7, 26-triazatetracyclo [19.3.1.12,6.18 ,12]-twenty-seven carbon-125,226,3,5,8,10,122716,21, 23-decaene, the structural formula of which is shown in the formula I. Pacritinib is an oral tyrosine kinase inhibitor, and mainly acts on Janus related kinase (JAK) and fms-like tyrosine kinase (FLT) to JAK2 (IC)5023nM) and FLT3 (IC)5022nM) has dual inhibitory activity. CTI biopharmaceuticals (CTI BioPharma) and Baxter International (Baxter International) in 2013 to achieve global authorization, cooperative development and commercialization of Pacritinib, obtained in the United states in 2014The Food and Drug Administration (FDA) rapidly assesses the eligibility of channels for the treatment of patients with high risk of myelofibrosis, including disease-related thrombocytopenia, currently in phase iii clinical studies. CTI biopharmaceutical company announced in 2020: the New Drug Application (NDA) for Pacritinib is planned to be submitted to the FDA for accelerated approval for the treatment of myelofibrosis and severe thrombocytopenia (platelet counts less than 50X 109/L) patients. In multiple trials, pacritiniib showed clinical benefit in treating these patients, with the potential to become a new treatment option for primary and second-line myelofibrosis patients. In view of the excellent clinical performance of Pacritinib, the research on the synthesis process of Pacritinib has important significance in reducing the production cost.
The synthesis route of the Pacritinib reported in the prior art can be summarized into the following two methods:
scheme one (formula ii): world patent WO2007058627, Chinese medical industry Journal of Pharmaceuticals 2015,46(12) and document J Med chem.2011 Jul 14; 54(13) 4638-58, which are characterized by the steps of coupling two terminal olefins via olefin metathesis to form a key trans double bond. The difference is only the introduction time of the side chain pyrrolidine and the optimization of the reaction condition. The original report (see document J Med chem.2011 Jul 14; 54(13):4638-58) shows that in the route, 2, 4-dichloropyrimidine, 3-hydroxymethyl-phenylboronic acid and 2-hydroxy-5-nitrobenzaldehyde are subjected to a series of reactions to respectively obtain an intermediate A and an intermediate B, the intermediate A and the intermediate B are subjected to aromatic nucleophilic substitution reaction, the obtained product is subjected to olefin metathesis reaction, and finally tetrahydropyrrole is introduced to prepare Pacritinib (I):
the synthesis method has the following defects: 1) in the reaction for generating C-C double bond, Glabra second generation (Grubbs 2nd) catalyst is used, the catalyst is prepared from noble metal ruthenium and complex ligand, the price is high, 2) the generated product has cis-trans isomer (trans/cis 85:15), the separation is difficult, the preparation amount is only milligram level, and the industrial production requirement is not met.
Scheme ii (formula iii): chinese patent document CN105017282 designs a synthetic route of Pacritinib, and the Pacritinib is prepared by carrying out cyclization reaction on an intermediate C and an intermediate D under the action of an alkali promoter. The intermediate C is prepared from the raw material 3-hydroxymethyl-acetophenone through condensation reaction and etherification reaction respectively, and the intermediate D is prepared from the raw material 2-hydroxy-5-nitrobenzaldehyde through etherification reaction, aldehyde group reduction, nitro group reduction and guanidine reaction.
The synthesis method has the following defects: 1) in the reaction route, the raw material 3-hydroxymethyl-acetophenone is expensive (1g/320USD), and is not suitable as the starting material of the synthesis route; 2) the guanidino group in intermediate D is unstable and easily decomposed under alkaline conditions, while an alkali promoter (a combination of potassium carbonate and potassium hydroxide or a combination of cesium carbonate and potassium hydroxide) is used in the cyclization step of intermediate C and intermediate D; 3) in the cyclization step of the intermediate C and the intermediate D, guanidino is required to react with the intermediate C to generate 2, 4-dichloropyrimidine fragments, hydroxymethyl is required to react with the intermediate C to perform etherification reaction for cyclization, and the reaction process is difficult to control due to a plurality of reaction sites.
Aiming at the defects of the existing process, the preparation method of Pacritinib which has the advantages of reasonable route, high reaction efficiency, mild condition, economy, environmental protection and simple synthetic route and is suitable for process production is developed, and the method has practical significance for specially solving the unmet requirements of myelofibrosis patients suffering from severe thrombocytopenia after coming into the market in the future.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a synthesis method of the JAK inhibitor Pacritinib, which has the advantages of reasonable route, high reaction efficiency, mild condition, economy, environmental protection, simple synthesis route and suitability for process production.
The invention is realized by the following technical scheme:
a method for synthesizing a JAK inhibitor Pacritinib comprises the following steps:
(1) synthesis of intermediate F: the raw materials of 2, 4-dichloropyrimidine and 3-formylphenylboronic acid undergo Suzuki coupling reaction under the catalysis of palladium acetate to obtain an intermediate F,
(2) synthesis of intermediate G: the intermediate 4 is obtained by etherification reaction of the raw material 2-hydroxy-5-nitrobenzaldehyde, and the intermediate G is obtained by reduction of nitro.
(3) Intermediate F and intermediate G are subjected to aromatic nucleophilic substitution to obtain intermediate 5, and then the 2-amino (Boc) of pyrimidine ring of intermediate 5 is reacted2Protecting by O to obtain an intermediate 6, and reducing by aldehyde group to obtain an intermediate E;
(4) the intermediate E and the raw material trans-1, 4-dibromo-2-butylene are subjected to etherification reaction to obtain an intermediate 7,
(5) intermediate 7 was reacted with tetrahydropyrrole to give pacritiniib.
The synthetic reaction route of Pacritinib is shown in the following formula IV:
compared with the existing synthesis process, the invention uses the intermediate E and the trans-1, 4-dibromo-2-butene to form the ring through the ether forming reaction, and has the advantages of cheap and easily obtained raw materials, mild reaction, no cis-configuration of the product and the like.
Preferably, in step (1), the synthesis of intermediate F is specifically as follows:
mixing 2, 4-dichloropyrimidine and 3-formylphenylboronic acid in a molar ratio of 1: adding the mixture into an aromatic hydrocarbon solvent according to the proportion of 1.0-1.2, adding alkali, triphenyl phosphorus and palladium acetate, and performing Suzuki coupling reaction at the temperature of 70-100 ℃ to obtain an intermediate F.
More preferably, the aromatic hydrocarbon solvent is a mixed solvent of 1, 4-dioxane, 1, 2-dimethoxyethane, toluene and absolute ethyl alcohol, and still more preferably, the aromatic hydrocarbon solvent is a mixed solvent of toluene and absolute ethyl alcohol in a volume ratio of 1:1.
Further preferably, the base is sodium carbonate, cesium carbonate or potassium hydroxide, and preferably, the base is sodium carbonate.
Further preferably, the reaction temperature is 70-90 ℃ and the reaction time is 20-26 h.
More preferably, the molar ratio of the 2, 4-dichloropyrimidine to the base is 1: 1.5-2.5, the molar ratio of the 2, 4-dichloropyrimidine to the triphenylphosphine is 1: 0.15-0.3, and the molar ratio of the 2, 4-dichloropyrimidine to the palladium acetate is 1: 0.02-0.06; the molar volume ratio of the 2, 4-dichloropyrimidine to the aromatic hydrocarbon solvent is as follows: (30-40) < 80-120 >, in mmol/mL.
Preferably, in the step (2), the etherification reaction is to dissolve 2-hydroxy-5-nitrobenzaldehyde in N, N-dimethylformamide, add 1, 2-dichloroethane and a base to the system, and perform reflux etherification reaction to obtain the intermediate 4.
Further preferred, the molar ratio of 2-hydroxy-5-nitrobenzaldehyde to 1, 2-dichloroethane is 1: 2.0-15.0 mol/volume ratio of 2-hydroxy-5-nitrobenzaldehyde to N, N-dimethylformamide is as follows: (25-40), (20-60) in mmol/mL.
Most preferably, the molar ratio of 2-hydroxy-5-nitrobenzaldehyde to 1, 2-dichloroethane is 1: 10.0.
further preferably, the alkali is sodium carbonate, potassium hydroxide or potassium carbonate.
Further preferred, the molar ratio of 2-hydroxy-5-nitrobenzaldehyde to base is 1: 1.0 to 5.0.
Further preferably, the reflux etherification reaction temperature is 80-130 ℃, preferably 120 ℃, and the reaction time is 20-26 h.
Preferably, in step (2) according to the present invention, the reduction of the nitro group to intermediate 4 with hydrazine hydrate is carried out in a molar ratio of 1: adding the mixture into tetrahydrofuran according to the proportion of 1.0-5.0, adding a Pd/C catalyst, and carrying out nitro reduction at 25-65 ℃ to obtain an intermediate G.
Further preferably, the molar volume ratio of the intermediate 4 to the tetrahydrofuran is: (2-6) (20-60) in mmol/mL.
Further preferably, the mass ratio of the Pd/C catalyst to the intermediate 4 is (0.1 to 0.5): (1-3).
Further preferably, in the step (2), the reduction reaction temperature of the nitro group is 40-60 ℃, and the reaction time is 1-5 h.
Preferably, in the step (3), the aromatic nucleophilic substitution reaction is that the intermediate F and the intermediate G are dissolved in n-butyl alcohol according to the molar ratio of 1.0-1.5: 1, and then acid is added to perform aromatic nucleophilic substitution to obtain the intermediate 5.
Further preferably, the acid is hydrochloric acid or trifluoroacetic acid or p-toluenesulfonic acid, preferably trifluoroacetic acid.
Further preferably, the molar volume ratio of the intermediate F to the n-butanol is as follows: (2-8), (20-60) in mmol/mL.
Further preferably, the molar volume ratio of the intermediate F to the acid is: (2 to 8), (1 to 5), in mmol/mL.
Further preferably, the aromatic nucleophilic substitution reaction temperature is 100-130 ℃, and the reaction time is 4-8 h.
Preferably according to the invention, in step (3), up (Boc)2The O protection is specifically as follows: intermediate 5 with (Boc)2O is added into the mixture in a molar ratio of 1: dissolving the mixture in dichloromethane in a ratio of 1.0-2.0, adding 4-dimethylaminopyridine and alkali, and carrying out nucleophilic substitution reaction to obtain an intermediate 6.
Further preferably, the molar volume ratio of the intermediate 5 to the dichloromethane is: (0.4-1.0): (40-60), unit mmol/mL.
More preferably, the molar ratio of the intermediate 5 to the 4-dimethylaminopyridine is 8.0-12.0: 1.
Further preferably, the base is sodium carbonate or triethylamine or sodium hydroxide, preferably the base is sodium carbonate.
More preferably, the molar ratio of the intermediate 5 to the base is 1:1 to 5.
Further preferably, the nucleophilic substitution reaction temperature is 40-70 ℃, and the reaction time is 4-10 h.
Preferably, in step (3), the reduction of the aldehyde group is specifically: intermediate 6 and sodium borohydride were added in a molar ratio of 1: dissolving the mixture in an alcohol organic solvent at a ratio of 2.0-3.0, and reducing aldehyde groups to obtain an intermediate E.
Further preferably, the alcohol organic solvent is tetrahydrofuran or dichloromethane or a mixed solvent of tetrahydrofuran and methanol;
most preferably, the alcohol organic solvent is a mixed solvent of tetrahydrofuran and methanol, and the volume ratio of the tetrahydrofuran to the methanol is 1:1.
Further preferably, the molar volume ratio of the intermediate 6 to the alcoholic organic solvent is: (0.3-0.8): (40-60) in mmol/mL.
Further preferably, the aldehyde group reduction reaction temperature is room temperature, and the reaction time is 1-5 h.
Preferably, according to the present invention, in step (4), the etherification reaction is: the intermediate E was reacted with trans-1, 4-dibromo-2-butene in a molar ratio of 1: adding the mixture into a polar organic solvent according to the proportion of 1.0-1.5, adding alkali, and carrying out Williams' etherification reaction to obtain an intermediate 7.
Further preferably, the polar organic solvent is tetrahydrofuran or dichloromethane or N, N-dimethylformamide, and the preferred polar organic solvent is tetrahydrofuran.
Further preferably, the molar volume ratio of the intermediate E to the polar organic solvent is: (0.1-0.5): (10-40) in mmol/mL.
Further preferably, the base is sodium hydroxide or sodium hydride or potassium hydroxide, preferably the base is sodium hydride;
further preferably, the molar ratio of intermediate E to base is 1: 2.0 to 3.0.
Further preferably, the Williams etherification reaction temperature is room temperature, and the reaction time is 4-10 h.
Preferably, in step (5), the intermediate 7 is reacted with pyrrolidine in a molar ratio of 1: adding the polar organic solvent into the mixture according to the proportion of 4.0-6.0, and reacting for 4-10 hours at the temperature of 60-90 ℃ to obtain the target object Pacritinib.
Further preferably, the polar organic solvent is tetrahydrofuran or dichloromethane or N, N-Dimethylacetamide (DMAC), and the preferred polar organic solvent is N, N-dimethylacetamide.
Further preferably, the molar volume ratio of the intermediate 7 to the polar organic solvent is: (0.3-0.6) < 30-50, unit mmol/mL.
More preferably, the reaction temperature is 80 ℃ and the reaction time is 6 h.
The invention has the technical characteristics and advantages that:
1. in contrast to the synthetic method of scheme one, scheme one cross-couples two terminal olefins to form one trans-olefin via olefin metathesis. The method uses olefin metathesis reaction to form ring, the reaction needs to be carried out in nitrogen atmosphere and has harsh reaction conditions, while the ring forming reaction is carried out by Williams etherification reaction with milder and simpler conditions, the room temperature stirring is carried out, the reaction conditions are mild, a noble metal catalyst is not needed, nitrogen gas is not needed to be filled for protection, the product does not have cis-configuration, the separation and purification are more convenient, the total reaction route is shortened from 9 steps to 8 steps, in addition, the cis-configuration can be generated in the reaction process of the first synthetic route, the separation with the polarity similar to that of a target object (trans-configuration) is difficult, the separation and purification are needed, and the preparation efficiency is low.
2. Compared with the synthetic method described in the second synthetic route, the raw materials of the invention, namely, 2, 4-dichloropyrimidine (25 g/35.25) and 3-formylphenylboronic acid (25 g/120), are cheaper and lower in cost than the raw material of the invention, namely, 3-hydroxymethyl-acetophenone (1 g/320) used in the second synthetic route, and are more suitable for enlarged production.
Detailed Description
The invention is further illustrated below with reference to specific examples of implementation. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. All equivalent changes or modifications made according to the present invention should be covered within the protection scope of the present invention.
2, 4-dichloropyrimidine, 3-formylphenylboronic acid, 2-hydroxy-5-nitrobenzaldehyde, and the like, available from Shanghai Bigdi pharmaceutical science and technology Limited; n, N-dimethylformamide, tetrahydrofuran, toluene and the like are purchased from national drug group chemical reagents, Inc.;
example 1
Preparation of 3- (2-chloropyrimidin-4-yl) benzaldehyde intermediate F
Dissolving 2, 4-dichloropyrimidine (5.00g,33.6mmol) and 3-formylphenylboronic acid (5.53g,36.92mmol) in a mixed solvent of toluene and absolute ethyl alcohol (40/40mL), adding sodium carbonate (7.11g,67.12mmol), triphenylphosphine (1.76g,6.71mmol) and palladium acetate (0.30g,1.34mmol), stirring at 80 ℃ for 24h under a nitrogen atmosphere, filtering to remove solid residues, evaporating toluene and absolute ethyl alcohol under reduced pressure to separate out a large amount of solids, filtering under reduced pressure, washing impurities (20mL) with ethyl acetate, collecting a filter cake to obtain 6.53g of a light yellow solid with a yield of 89.0%;1H NMR(400MHz,DMSO-d6)δ10.15(s,1H),8.91(d,J＝5.3Hz,1H),8.72(t,J＝2.0Hz,1H),8.51(d,J＝8.1Hz,1H),8.27(d,J＝5.3Hz,1H),8.16–8.11(m,1H),7.83(q,J＝7.7,7.3Hz,1H).
example 2
Preparation of 5-amino-2- (2-chloroethoxy) benzaldehyde intermediate 4
2-hydroxy-5-nitrobenzaldehyde (5.00g,29.92mmol) was dissolved in N, N-dimethylformamide (50mL), 1, 2-dichloroethane (25.22mL,299.19mmol) and potassium carbonate (8.27g,59.84 mmol) were added, and the mixture was stirred and refluxed at 120 ℃ for 24 hours, after completion of the reaction, the solid residue was removed by filtration, 1, 2-dichloroethane was evaporated under reduced pressure, water was added, extraction was performed 3 times with ethyl acetate (20 mL. times.3), the organic phases were combined, washed successively with water and saturated brine (50mL), dried and concentrated. Column chromatography (PE: EA ═ 15%) gave 5.15g of a pale yellow solid, yield: 74.9 percent;1H NMR(400MHz,DMSO-d6)δ10.39(s,1H),8.51(dd,J＝9.2,3.0Hz,1H),8.43(dd,J＝2.9,1.0Hz,1H),7.52(d,J＝9.3Hz,1H),4.77–4.57(m,2H),4.08(dd,J＝5.8,4.3Hz,2H).
example 3
Preparation of 5-amino-2- (2-chloroethoxy) benzaldehyde intermediate G
Dissolving intermediate 4(1.00g,4.36mmol) in tetrahydrofuran (30mL), adding Pd/C (0.20g), dropwise adding hydrazine hydrate (0.22g,4.36mmol) at 40 deg.C, heating to 55 deg.C, stirring and refluxing for 3h, filtering to remove solid residue, adding water, extracting with ethyl acetate for 3 times (20mL × 3)) And mixing organic phases, washing the organic phase with water and saturated salt water successively, drying and concentrating. Column chromatography (PE: EA ═ 35%) gave 0.59g of a yellow-green solid, yield: 68.2 percent;1H NMR(400MHz,DMSO-d6)δ8.90(d,J＝1.1Hz,1H),7.27(d,J＝2.8Hz,1H),6.89(d,J＝8.8Hz,1H),6.72(dd,J＝8.7,3.0Hz,1H),4.93(s,2H),4.22(t,J＝5.0Hz,2H),3.99–3.91(m,2H).
example 4
Preparation of 2- (2-chloroethoxy) -5- [ (4- (3-formylphenyl) pyrimidin-2-yl) amino ] benzaldehyde intermediate 5
Dissolving intermediate F (0.85G,3.91mmol) and intermediate G (0.65G,3.26mmol) in n-butanol (50mL), adding trifluoroacetic acid (2mL), stirring and refluxing at 110 ℃ for 6h, after the reaction is finished, evaporating n-butanol under reduced pressure, adding water, extracting 3 times with ethyl acetate (20 mL. times.3), combining organic phases, washing the organic phases with water and saturated salt water (50mL) in turn, drying and concentrating. Column chromatography (PE: EA ═ 45%) gave 0.90g of a yellow solid, yield: 72.3 percent;1H NMR(400MHz,DMSO-d6)δ10.47(s,1H),10.18(s,1H),9.86(s,1H),8.77(t,J＝1.8Hz,1H),8.63(d,J＝5.3Hz,1H),8.52(dt,J＝7.8,1.6Hz,1H),8.46(d,J＝3.2Hz,1H),8.08(dt,J＝7.7,1.4Hz,1H),7.96(dd,J＝9.0,2.9Hz,1H),7.79(t,J＝7.7Hz,1H),7.54(d,J＝5.1Hz,1H),7.28(d,J＝9.0Hz,1H),4.51–4.39(m,2H),4.03(dd,J＝5.9,4.3Hz,2H).
example 5
Preparation of intermediate 6
Intermediate 5(0.30g,0.79mmol), (Boc)2O (0.34g,1.57mmol) and 4-dimethylaminopyridine (17mg,0.08mmol) were dissolved in dichloromethane (50mL), sodium carbonate (0.16g,1.57mmol) was added, the reaction was stirred at 60 ℃ for 6h, after completion, water was added and the reaction was quenched, extracted 3 times with dichloromethane (20 mL. times.3), the organic phases were combined, washed successively with water and saturated brine (50mL), dried, concentrated, and subjected to column chromatography (PE: EA. RTM.: 7%) to give 0.31g of a yellow solid as intermediate 6-tert-butyl [4- (2-chloroethoxy) -3-formylphenyl group][4- (3-formylphenyl) pyrimidin-2-yl]Carbamate, yield: 81.4 percent;1H NMR(400MHz,DMSO-d6)δ10.40(s,1H),10.12(s,1H),8.84(d,J＝5.3Hz,1H),8.70(t,J＝1.8Hz,1H),8.48(dt,J＝7.8,1.5Hz,1H),8.11(dt,J＝7.6,1.3Hz,1H),8.03(d,J＝5.3Hz,1H),7.81(t,J＝7.7Hz,1H),7.64–7.49(m,2H),7.31(d,J＝8.9Hz,1H),4.60–4.41(m,2H),4.11–4.00(m,2H),1.45(s,9H).
example 6
Preparation of intermediate E
Dissolving intermediate 6(0.31g,0.64mmol) in a mixed solvent of tetrahydrofuran and methanol (20/20mL), adding sodium borohydride (54mg,1.42mmol), stirring at room temperature for 3h, after the reaction is finished, evaporating the solvent under reduced pressure, adding water, extracting with ethyl acetate for 3 times (20 mL. times.3), combining organic phases, washing the organic phase with water and saturated brine (50mL), drying and concentrating. 0.24g of a clear solid is obtained as intermediate E, tert-butyl [4- (2-chloroethoxy) -3- (hydroxymethyl) phenyl][4- (3- (hydroxymethyl) phenyl) pyrimidin-2-yl group]Carbamate, yield: 77.2 percent;1H NMR(400MHz,DMSO-d6)δ8.74(d,J＝5.3Hz,1H),8.18(s,1H),8.03(d,J＝6.7Hz,1H),7.85(d,J＝5.4Hz,1H),7.51(d,J＝6.8Hz,2H),7.28(d,J＝2.4Hz,1H),7.08(dd,J＝8.7,2.4Hz,1H),6.99–6.90(m,1H),5.36(t,J＝5.7Hz,1H),5.14(t,J＝5.7Hz,1H),4.61(d,J＝5.9Hz,2H),4.55(d,J＝5.7Hz,2H),4.25(t,J＝5.1Hz,2H),3.93(t,J＝5.1Hz,2H),1.43(d,J＝3.5Hz,9H).
example 7
Preparation of intermediate 7
Intermediate E (0.18g,0.37mmol) and trans-1, 4-dibromo-2-butene (79mg,0.37mmol) were dissolved in tetrahydrofuran (20mL), sodium hydride (18mg,0.74mmol) was added, stirring was performed at room temperature for 6 hours, after completion of the reaction, the solvent was evaporated under reduced pressure, water was added, extraction was performed 3 times with ethyl acetate (20 mL. times.3), the organic phases were combined, washed with water, saturated brine (50mL) successively, dried, and concentrated. Column chromatography (PE: EA ═ 10%) gave 64mg of a yellow solid as intermediate 7(E) -44- (2-chloroethoxy) -6, 11-dioxa-3-aza-2 (4,2) -pyrimidin-1, 4(1,3) -dibenzocyclodecan-8-ene, yield: 39.4 percent;1H NMR(400MHz,DMSO-d6)δ9.56(s,1H),8.56–8.51(m,2H),8.18(s,1H),8.02(d,J＝5.9Hz,1H),7.56(dd,J＝4.8,1.8Hz,2H),7.40(d,J＝5.3Hz,1H),7.12(dd,J＝8.8,2.9Hz,1H),7.00(d,J＝8.8Hz,1H),5.88–5.82(m,1H),5.73–5.66(m,1H),4.56(s,2H),4.53(s,2H),4.25(dd,J＝6.0,4.4Hz,2H),4.07(d,J＝5.6Hz,2H),4.00(d,J＝5.4Hz,2H),3.94(dd,J＝5.9,4.4Hz,2H).
example 8
Preparation of Pacritinib
Dissolving intermediate 7(0.18g,0.41mmol) in N, N-dimethylacetamide (40mL), adding tetrahydropyrrole (2mL) dropwise, stirring at 80 ℃ for 6h, after the reaction is finished, adding water for quenching, extracting 3 times (20 mL. times.3) with ethyl acetate, combining organic phases, washing the organic phases with water and saturated brine (50mL), drying and concentrating. Column chromatography (DCM: EA ═ 7%) gave 0.18g of pacritiniib as a pale yellow solid, yield: 93.6 percent;1H NMR(400MHz,DMSO-d6)δ9.54(s,1H),8.53(t,J＝4.3Hz,2H),8.18(s,1H),8.06–7.98(m,1H),7.59–7.50(m,2H),7.39(d,J＝5.3Hz,1H),7.12(dd,J＝8.8,2.8Hz,1H),6.97(d,J＝8.8Hz,1H),5.85(dt,J＝15.6,5.5Hz,1H),5.70(dt,J＝15.8,6.0Hz,1H),4.56(s,2H),4.49(s,2H),4.11–4.03(m,4H),4.00(d,J＝5.5Hz,2H),2.86(s,2H),2.63(s,4H),1.72(p,J＝3.1Hz,4H).
Claims (10)
1. a method for synthesizing a JAK inhibitor Pacritinib comprises the following steps:
(1) synthesis of intermediate F: the raw materials of 2, 4-dichloropyrimidine and 3-formylphenylboronic acid undergo Suzuki coupling reaction under the catalysis of palladium acetate to obtain an intermediate F,
(2) synthesis of intermediate G: the intermediate 4 is obtained by etherification reaction of the raw material 2-hydroxy-5-nitrobenzaldehyde, and the intermediate G is obtained by reduction of nitro.
(3) Intermediate F and intermediate G are subjected to aromatic nucleophilic substitution to obtain intermediate 5, and then the 2-amino (Boc) of pyrimidine ring of intermediate 5 is reacted2Protecting by O to obtain an intermediate 6, and reducing by aldehyde group to obtain an intermediate E;
(4) the intermediate E and the raw material trans-1, 4-dibromo-2-butylene are subjected to etherification reaction to obtain an intermediate 7,
(5) intermediate 7 was reacted with tetrahydropyrrole to give pacritiniib.
2. The synthesis method according to claim 1, wherein in step (1), the synthesis of intermediate F is specifically as follows:
mixing 2, 4-dichloropyrimidine and 3-formylphenylboronic acid in a molar ratio of 1: adding the mixture into an aromatic hydrocarbon solvent according to the proportion of 1.0-1.2, adding alkali, triphenyl phosphorus and palladium acetate, and performing Suzuki coupling reaction at the temperature of 70-100 ℃ to obtain an intermediate F.
3. The synthesis method according to claim 2, wherein the aromatic hydrocarbon solvent is a mixed solvent of 1, 4-dioxane, 1, 2-dimethoxyethane, toluene and absolute ethyl alcohol, and more preferably, the aromatic hydrocarbon solvent is a mixed solvent of toluene and absolute ethyl alcohol in a volume ratio of 1: 1;
the alkali is sodium carbonate, cesium carbonate or potassium hydroxide;
the reaction temperature is 70-90 ℃, and the reaction time is 20-26 h;
the molar ratio of the 2, 4-dichloropyrimidine to the alkali is 1: 1.5-2.5, the molar ratio of the 2, 4-dichloropyrimidine to the triphenyl phosphine is 1: 0.15-0.3, and the molar ratio of the 2, 4-dichloropyrimidine to the palladium acetate is 1: 0.02-0.06; the molar volume ratio of the 2, 4-dichloropyrimidine to the aromatic hydrocarbon solvent is as follows: (30-40) < 80-120 >, in mmol/mL.
4. The synthesis method according to claim 1, wherein in the step (2), the etherification reaction is performed by dissolving 2-hydroxy-5-nitrobenzaldehyde in N, N-dimethylformamide, adding 1, 2-dichloroethane and a base into the system, and performing reflux etherification reaction to obtain the intermediate 4.
5. The synthesis according to claim 4, characterized in that the molar ratio of 2-hydroxy-5-nitrobenzaldehyde to 1, 2-dichloroethane is 1: 2.0-15.0 mol/volume ratio of 2-hydroxy-5-nitrobenzaldehyde to N, N-dimethylformamide is as follows: (25-40) (20-60) in mmol/mL,
the alkali is sodium carbonate, potassium hydroxide or potassium carbonate,
molar ratio of 2-hydroxy-5-nitrobenzaldehyde to base 1: 1.0 to 5.0;
the reflux etherification reaction temperature is 80-130 ℃, and the reaction time is 20-26 h.
6. The synthesis method of claim 1, wherein in the step (2), the reduction reaction of the nitro group is that the intermediate 4 and hydrazine hydrate are reacted in a molar ratio of 1: adding the mixture into tetrahydrofuran according to the proportion of 1.0-5.0, adding a Pd/C catalyst, and carrying out nitro reduction at 25-65 ℃ to obtain an intermediate G;
the molar volume ratio of the intermediate 4 to the tetrahydrofuran is as follows: (2-6) (20-60) in mmol/mL;
the mass ratio of the Pd/C catalyst to the intermediate 4 is (0.1-0.5): (1-3);
the reduction reaction temperature of the nitro is 40-60 ℃, and the reaction time is 1-5 h.
7. The synthesis method according to claim 1, wherein in the step (3), the aromatic nucleophilic substitution reaction is that the intermediate F and the intermediate G are dissolved in n-butanol according to the molar ratio of 1.0-1.5: 1, and then acid is added to perform aromatic nucleophilic substitution to obtain the intermediate 5, top (Boc)2The O protection is specifically as follows: intermediate 5 with (Boc)2O is added into the mixture in a molar ratio of 1: dissolving the mixture in dichloromethane in a ratio of 1.0-2.0, adding 4-dimethylaminopyridine and alkali, and carrying out nucleophilic substitution reaction to obtain an intermediate 6, wherein the aldehyde group reduction specifically comprises the following steps: intermediate 6 and sodium borohydride were added in a molar ratio of 1: dissolving the mixture in an alcohol organic solvent at a ratio of 2.0-3.0, and reducing aldehyde groups to obtain an intermediate E.
8. The synthesis method according to claim 7, characterized in that the acid is hydrochloric acid or trifluoroacetic acid or p-toluenesulfonic acid,
the molar volume ratio of the intermediate F to the n-butanol is as follows: (2-8) (20-60) in mmol/mL,
the molar volume ratio of the intermediate F to the acid is as follows: (2 to 8), (1 to 5) in units of mmol/mL,
the reaction temperature of the aromatic nucleophilic substitution is 100-130 ℃, the reaction time is 4-8 h,
the molar volume ratio of the intermediate 5 to the dichloromethane is as follows: (0.4-1.0) < 40-60 >, unit mmol/mL,
the molar ratio of the intermediate 5 to the 4-dimethylaminopyridine is 8.0-12.0: 1,
the alkali is sodium carbonate or triethylamine or sodium hydroxide,
the molar ratio of the intermediate 5 to the alkali is 1: 1-5,
the nucleophilic substitution reaction temperature is 40-70 ℃, the reaction time is 4-10h,
the alcohol organic solvent is tetrahydrofuran or dichloromethane or a mixed solvent of tetrahydrofuran and methanol;
the molar volume ratio of the intermediate 6 to the alcohol organic solvent is as follows: (0.3-0.8) < 40-60 >, unit mmol/mL,
the aldehyde group reduction reaction temperature is room temperature, and the reaction time is 1-5 h.
9. The synthesis method according to claim 1, wherein in the step (4), the etherification reaction is: the intermediate E was reacted with trans-1, 4-dibromo-2-butene in a molar ratio of 1: adding the mixture into a polar organic solvent according to the proportion of 1.0-1.5, adding alkali, and carrying out Williams' etherification reaction to obtain an intermediate 7;
the polar organic solvent is tetrahydrofuran or dichloromethane or N, N-dimethylformamide,
the molar volume ratio of the intermediate E to the polar organic solvent is as follows: (0.1-0.5) (10-40) in mmol/mL,
the alkali is sodium hydroxide or sodium hydride or potassium hydroxide, preferably the alkali is sodium hydride;
molar ratio of intermediate E to base 1: 2.0 to 3.0 parts by weight,
the Williams etherification reaction temperature is room temperature, and the reaction time is 4-10 h.
10. The synthesis method according to claim 1, wherein in the step (5), the intermediate 7 is reacted with pyrrolidine in a molar ratio of 1: adding the polar organic solvent into the mixture according to the proportion of 4.0-6.0, and reacting for 4-10 hours at the temperature of 60-90 ℃ to obtain the target object Pacritinib.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101360751A (en) * | 2005-11-16 | 2009-02-04 | S*Bio私人有限公司 | Oxygen linked pyrimidine derivatives |
| CN105017282A (en) * | 2015-08-28 | 2015-11-04 | 苏州明锐医药科技有限公司 | Pacritinib preparing method |
| CN105061467A (en) * | 2015-08-28 | 2015-11-18 | 苏州立新制药有限公司 | Method for preparing pacritinib |
| KR20180020112A (en) * | 2016-08-17 | 2018-02-27 | 서울대학교산학협력단 | Immunosuppression composition comprising JAK inhibitor |
| CN113603708A (en) * | 2021-07-27 | 2021-11-05 | 中国药科大学 | Preparation method and application of novel CDK9 inhibitor with macrocyclic framework structure |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101360751A (en) * | 2005-11-16 | 2009-02-04 | S*Bio私人有限公司 | Oxygen linked pyrimidine derivatives |
| CN105017282A (en) * | 2015-08-28 | 2015-11-04 | 苏州明锐医药科技有限公司 | Pacritinib preparing method |
| CN105061467A (en) * | 2015-08-28 | 2015-11-18 | 苏州立新制药有限公司 | Method for preparing pacritinib |
| KR20180020112A (en) * | 2016-08-17 | 2018-02-27 | 서울대학교산학협력단 | Immunosuppression composition comprising JAK inhibitor |
| CN113603708A (en) * | 2021-07-27 | 2021-11-05 | 中国药科大学 | Preparation method and application of novel CDK9 inhibitor with macrocyclic framework structure |
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