WO2016127915A1 - 伊布替尼的制备方法 - Google Patents
伊布替尼的制备方法 Download PDFInfo
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- WO2016127915A1 WO2016127915A1 PCT/CN2016/073537 CN2016073537W WO2016127915A1 WO 2016127915 A1 WO2016127915 A1 WO 2016127915A1 CN 2016073537 W CN2016073537 W CN 2016073537W WO 2016127915 A1 WO2016127915 A1 WO 2016127915A1
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- Prior art keywords
- compound
- formula
- potassium
- sodium
- ibufenib
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- 0 *C(N(CCC1)C[C@@]1[n]1nc(*)c2c(N)ncnc12)=O Chemical compound *C(N(CCC1)C[C@@]1[n]1nc(*)c2c(N)ncnc12)=O 0.000 description 11
- XYFPWWZEPKGCCK-GOSISDBHSA-N C=CC(N(CCC1)C[C@@H]1[n](c1ncnc(N)c11)nc1-c(cc1)ccc1Oc1ccccc1)=O Chemical compound C=CC(N(CCC1)C[C@@H]1[n](c1ncnc(N)c11)nc1-c(cc1)ccc1Oc1ccccc1)=O XYFPWWZEPKGCCK-GOSISDBHSA-N 0.000 description 2
- KKXJSUAAPOQJSI-ZCFIWIBFSA-N Nc1c2c(Br)n[n]([C@H]3CNCCC3)c2ncn1 Chemical compound Nc1c2c(Br)n[n]([C@H]3CNCCC3)c2ncn1 KKXJSUAAPOQJSI-ZCFIWIBFSA-N 0.000 description 2
- XYBLNTXJBVNSIS-ZCFIWIBFSA-N Nc1c2c(I)n[n]([C@H]3CNCCC3)c2ncn1 Chemical compound Nc1c2c(I)n[n]([C@H]3CNCCC3)c2ncn1 XYBLNTXJBVNSIS-ZCFIWIBFSA-N 0.000 description 2
- JIDJAGAYQHJZOR-UHFFFAOYSA-N Bc(cc1)ccc1Oc1ccccc1 Chemical compound Bc(cc1)ccc1Oc1ccccc1 JIDJAGAYQHJZOR-UHFFFAOYSA-N 0.000 description 1
- CTFXOUXSBGMYTJ-MRVPVSSYSA-N C=CC(N(CCC1)C[C@@H]1[n](c1ncnc(N)c11)nc1I)=O Chemical compound C=CC(N(CCC1)C[C@@H]1[n](c1ncnc(N)c11)nc1I)=O CTFXOUXSBGMYTJ-MRVPVSSYSA-N 0.000 description 1
- GPSQYTDPBDNDGI-MRXNPFEDSA-N Nc1c(c(-c(cc2)ccc2Oc2ccccc2)n[n]2[C@H]3CNCCC3)c2ncn1 Chemical compound Nc1c(c(-c(cc2)ccc2Oc2ccccc2)n[n]2[C@H]3CNCCC3)c2ncn1 GPSQYTDPBDNDGI-MRXNPFEDSA-N 0.000 description 1
- XXBJBOWLTYFSGL-MRVPVSSYSA-N Nc1c2c(Br)n[n]([C@H](CCC3)CN3C(CCBr)=O)c2ncn1 Chemical compound Nc1c2c(Br)n[n]([C@H](CCC3)CN3C(CCBr)=O)c2ncn1 XXBJBOWLTYFSGL-MRVPVSSYSA-N 0.000 description 1
- VNQLJXNKOGKTFO-MRVPVSSYSA-N Nc1c2c(I)n[n]([C@H](CCC3)CN3C(CCBr)=O)c2ncn1 Chemical compound Nc1c2c(I)n[n]([C@H](CCC3)CN3C(CCBr)=O)c2ncn1 VNQLJXNKOGKTFO-MRVPVSSYSA-N 0.000 description 1
- KFXUHRXGLWUOJT-UHFFFAOYSA-N OB(c(cc1)ccc1Oc1ccccc1)O Chemical compound OB(c(cc1)ccc1Oc1ccccc1)O KFXUHRXGLWUOJT-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- This application relates to the field of medicinal chemistry.
- the present application relates to a process for the preparation of Ibrutinib (trade name: Imbruvica) and an intermediate for the preparation of itibinib.
- Ibbutinib is an oral Bruton's tyrosine kinase (BTK) inhibitor and is used in pre-treatment of mantle cell lymphoma (MCL), pre-treatment of chronic lymphocytic leukemia and carrying Del 17p removes the treatment of mutant chronic lymphocytic leukemia (CLL).
- BTK Bruton's tyrosine kinase
- CN101610676A discloses starting from 4-phenoxybenzoic acid, condensing with malononitrile after chlorination, and then cyclizing with anhydrous hydrazine to obtain a pyrazole intermediate, followed by cyclization with formamide to obtain 4-aminopyridinium.
- the oxazo[3,4-d]pyrimidine nucleus is obtained by condensation reaction with a chiral alcohol, de Boc protecting group and acrylation.
- the synthesis route is as follows:
- the synthetic route is tedious and has many steps.
- the yield of the light-delay reaction step is low (34%), the total yield is only 8.1%, and
- the triphenylphosphine resin, which is not easy to obtain, is finally purified by chromatography to obtain ibufenib, which makes the route industrialized with high cost and complicated operation.
- CN103121999A discloses a condition in which 3-bromo-4-aminopyrazolo[3,4-d]pyrimidine is used as a starting material, followed by coupling with 4-phenoxybenzeneboronic acid via Suzuki reaction, and using cesium carbonate as a base.
- Ilbutinib is obtained by condensation of the lower and chiral alcohols, protection by trifluoroacetyl group, de Boc protecting group, acrylylation and de-trifluoroacetyl group protection.
- the synthetic route is as follows:
- WO2014022390A1 reports the preparation of intermediate 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine by iodo generation starting from 4-aminopyrazolo[3,4-d]pyrimidine. And then, by Suzuki reaction, coupled with 4-phenoxybenzeneboronic acid, condensation reaction with chiral alcohol, and then deprotected by hydrochloric acid to form salt, and finally obtained by acrylation to obtain ibufenib, synthetic route As follows:
- the catalyst used in the Suzuki reaction of this route has a high dosage of tetrakistriphenylphosphine palladium and a reaction time of up to 24 hours; a long delay reaction step, a low yield (38%), and a total route yield of only 9.3%, and requires Chromatographic purification is not suitable for industrial production.
- acryloyl chloride usually contains 1% to 3% of 3-chloropropionyl chloride, which causes the presence of 3-chloropropionylated impurities in the product ibufenib, resulting in difficulty in purification and difficulty in industrial application.
- the application provides a method for preparing ibu brinib, which comprises the following steps:
- Step 1 using a compound of formula 1 as a starting material, and reacting a compound of formula 2 in the presence of a base to form a compound of formula 3,
- Step 2 the compound of formula 3 is reacted with a compound of formula 4 in the presence of a base and a catalyst to form ibunotetin.
- X 1 is each independently selected from Cl, Br or I, preferably Cl or Br
- X 2 is independently selected from Cl or Br
- R' is selected from X 3 are each independently selected from Cl, Br or I, preferably Cl or Br.
- the present application provides another method for preparing ibu brinib, which comprises the following steps:
- Step 1 the compound of formula 1 is reacted with a compound of formula 4 in the presence of a base and a catalyst to form a compound of formula 8,
- Step 2 the compound of formula 8 is reacted with a compound of formula 2-1 in the presence of a base to form ibunotetin.
- X 1 are each independently selected from the group consisting of Cl, Br or I, preferably Cl or Br; X 2 are each independently selected from Cl or Br.
- the present application provides an intermediate compound as shown below which can be used to prepare ibufenib:
- X 1 and X 3 are each independently selected from Cl, Br or I.
- the application provides the use of an intermediate compound as shown below for the preparation of ibunotetin:
- X 1 and X 3 are each independently selected from Cl, Br or I.
- references to “an embodiment” or “an embodiment” or “in another embodiment” or “in certain embodiments” throughout this specification are meant to be included in the at least one embodiment.
- the appearances of the phrase “in one embodiment” or “in an embodiment” or “in another embodiment” or “in some embodiments” are not necessarily all referring to the same embodiment.
- the particular elements, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
- a reaction including a “catalyst” includes a catalyst, or two or more catalysts.
- the term “or” is generally used in its meaning including “and/or” unless it is specifically defined otherwise.
- the application provides a preparation method of Ibubinib, which comprises the following steps:
- Step 1 using a compound of formula 1 as a starting material, and reacting a compound of formula 2 in the presence of a base to form a compound of formula 3,
- Step 2 the compound of formula 3 is reacted with a compound of formula 4 in the presence of a base and a catalyst to form ibunotetin.
- X 1 is each independently selected from Cl, Br or I, preferably Cl or Br
- X 2 is independently selected from Cl or Br
- R' is selected from X 3 are each independently selected from Cl, Br or I, preferably Cl or Br.
- the amount of the compound of formula 2 is from 0.9 to 2 equivalents, preferably from 1 to 1.2 equivalents, relative to the amount of the compound of formula 1.
- the base is an inorganic base and/or an organic base
- the inorganic base includes, but is not limited to, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide. , potassium hydroxide, potassium hydride or sodium hydride, etc.
- organic bases include, but are not limited to, triethylamine, lutidine, diisopropylethylamine or 1,8-diazabicyclo[5.4.0] eleven Carbon-7-ene or the like; preferably an inorganic base, more preferably sodium hydrogencarbonate and potassium hydrogencarbonate.
- the amount of the base relative to the amount of the compound of formula 1 is from 1 to 5 equivalents, preferably from 1.5 to 3 equivalents, more preferably 2 equivalents.
- the reaction solvent is a polar aprotic solvent, preferably tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, acetonitrile or acetone, etc., more preferably 2 -methyltetrahydrofuran.
- the amount of the compound of formula 4 is from 1 to 3 equivalents, preferably from 1.2 to 2 equivalents, more preferably 1.5 equivalents, to the compound of formula 3.
- the catalyst in step 2, is selected from the group consisting of Pd(PPh 3 ) 4 , PdCl 2 (PPh 3 ) 2 , PdCl 2 (PhCN) 2 , Pd(OAc) 2 , Pd/C Or PdCl 2 (dppf) 2 or the like, preferably Pd(PPh 3 ) 4 .
- the amount of the catalyst is from 0.001 to 0.1 equivalents, preferably from 0.005 to 0.05 equivalents, more preferably 0.01 equivalents, relative to the amount of the compound of formula 3.
- the base is an inorganic base, preferably potassium carbonate, sodium carbonate, cesium carbonate, potassium acetate, sodium acetate, potassium phosphate, sodium phosphate, sodium hydrogencarbonate, potassium hydrogencarbonate.
- the amount of the base relative to the amount of the compound of formula 3 is from 1 to 5 equivalents, preferably from 2 to 4 equivalents, more preferably from 3 to 3.5 equivalents.
- the reaction solvent is a mixed solvent of a polar aprotic solvent and water, preferably tetrahydrofuran, 1,4-dioxane, acetonitrile, acetone, N,N-dimethyl a mixed solvent with water such as carbamide (DMF), dimethyl sulfoxide, N-methylpyrrolidone or ethylene glycol dimethyl ether, more preferably 1,4-dioxane with water or ethylene glycol A mixed solvent of ether and water.
- a mixed solvent of a polar aprotic solvent and water preferably tetrahydrofuran, 1,4-dioxane, acetonitrile, acetone, N,N-dimethyl a mixed solvent with water such as carbamide (DMF), dimethyl sulfoxide, N-methylpyrrolidone or ethylene glycol dimethyl ether, more preferably 1,4-dioxane with water or ethylene glycol A mixed solvent of ether and water.
- the reaction temperature is 15 ° C or lower, preferably -10 ° C to 5 ° C, more preferably -5 ° C to 0 ° C.
- the reaction temperature is from 60 ° C to 120 ° C, preferably from 80 ° C to 100 ° C.
- Yet another aspect of the present application provides another method of preparing ibunoteini comprising the steps of:
- Step 1 the compound of formula 1 is reacted with a compound of formula 4 in the presence of a base and a catalyst to form a compound of formula 8,
- Step 2 the compound of formula 8 is reacted with a compound of formula 2-1 in the presence of a base to form ibunotetin.
- X 1 are each independently selected from the group consisting of Cl, Br or I, preferably Cl or Br; X 2 are each independently selected from Cl or Br.
- the amount of the compound of Formula 4 is from 1 to 3 equivalents, preferably from 1.2 to 2 equivalents, more preferably 1.5 equivalents to the amount of the compound of Formula 1.
- the catalyst is selected from the group consisting of Pd(PPh 3 ) 4 , PdCl 2 (PPh 3 ) 2 , PdCl 2 (PhCN) 2 , Pd(OAc) 2 , Pd/C or PdCl 2 (dppf 2, etc., preferably Pd(PPh 3 ) 4 .
- the amount of the catalyst is from 0.001 to 0.1 equivalents, preferably from 0.005 to 0.05 equivalents, more preferably 0.01 equivalents, relative to the amount of the compound of formula 1.
- the base used in the step 1 is an inorganic base, preferably potassium carbonate, sodium carbonate, cesium carbonate, potassium acetate, sodium acetate, potassium phosphate, sodium phosphate, sodium hydrogencarbonate, potassium hydrogencarbonate, Sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride, more preferably potassium phosphate or potassium carbonate.
- the amount of the base used in the step 1 is from 1 to 5 equivalents, preferably from 2 to 4 equivalents, more preferably from 3 to 3.5 equivalents, to the amount of the compound of the formula 1.
- the reaction solvent used in the step 1 is a mixed solvent of a polar aprotic solvent and water, preferably tetrahydrofuran, 1,4-dioxane, acetonitrile, acetone, N, N-di a mixed solvent of water such as methylformamide (DMF), dimethyl sulfoxide, N-methylpyrrolidone or ethylene glycol dimethyl ether, more preferably 1,4-dioxane with water or ethylene glycol a mixed solvent of methyl ether and water.
- a mixed solvent of a polar aprotic solvent and water preferably tetrahydrofuran, 1,4-dioxane, acetonitrile, acetone, N, N-di a mixed solvent of water such as methylformamide (DMF), dimethyl sulfoxide, N-methylpyrrolidone or ethylene glycol dimethyl ether, more preferably 1,4-dioxane with water or ethylene glycol
- the amount of the compound of the formula 2-1 is from 0.9 to 2 equivalents, preferably from 1 to 1.2 equivalents, to the amount of the compound of the formula 8.
- the base used in the step 2 is an inorganic base and/or an organic base, wherein the inorganic base is selected from the group consisting of potassium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, and hydroxide. Potassium, potassium hydride or sodium hydride; the organic base is selected from the group consisting of triethylamine, lutidine, diisopropylethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene Etc., preferably an inorganic base, more preferably sodium hydrogencarbonate and potassium hydrogencarbonate.
- the inorganic base is selected from the group consisting of potassium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, and hydroxide. Potassium, potassium hydride or sodium hydride
- the organic base is selected from the group consisting of triethylamine, lutidine, diisopropylethylamine or 1,8-diaza
- the amount of the base used in the step 2 is from 1 to 5 equivalents, preferably from 1.5 to 3 equivalents, more preferably 2 equivalents, to the amount of the compound of the formula 8.
- the reaction solvent used in the step 2 is a polar aprotic solvent, preferably tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, acetonitrile or acetone, etc., more preferably 2-methyltetrahydrofuran.
- the reaction temperature is from 60 ° C to 120 ° C, preferably from 80 ° C to 100 ° C.
- the reaction temperature is 15 ° C or lower, preferably -10 ° C to 5 ° C, more preferably -5 ° C to 0 ° C.
- the method of preparing ibunotetin described herein further comprises the steps of: preparing a compound of formula 1:
- the compound of formula 5 is reacted with a compound of formula 6 in the presence of a photoreaction reagent to form a compound of formula 7, and then the compound of formula 7 is removed in the presence of an acid to form a compound of formula 1:
- R is an amino protecting group
- X 1 is each independently selected from the group consisting of Cl, Br or I, preferably Cl or Br.
- the amount of the compound of the formula 6 is from 0.5 to 3 equivalents, preferably from 1 to 2 equivalents, more preferably 1.5 equivalents, to the amount of the compound of the formula 5.
- the photolatent reaction reagent is selected from a first reagent selected from the group consisting of triphenylphosphine (TPP), tributylphosphine (TBP) or trimethylphosphine (TMP) and is selected from the group consisting of azo Diisopropyl dicarboxylate (DIAD), di-tert-butyl azodicarboxylate (DBAD), diethyl azodicarboxylate (DEAD), di-p-chlorobenzyl azodicarboxylate (DCAD), 1,1' -(Azodicarbyl)dipiperidine (ADDP), N,N,N',N'-tetraisopropylazodicarboxyamide (TIPA), N,N,N',N'-tetra Azo azocarboxamide (TMAD) or 4,7-dimethyl-3,4,5,6,7,8-hexahydro-1,2,4,7-tetraazax
- TPP tripheny
- the amount of the first reagent and the amount of the second reagent in the photosensitivity reagent are equimolar to each other, and each of the compounds of Formula 5 is 1-5 equivalents, preferably 2 5 equivalents, more preferably 3-4 equivalents.
- the solvent for preparing the compound of Formula 7 is selected from a polar aprotic solvent or water, preferably tetrahydrofuran (THF), N,N-dimethylformamide, dimethyl sulfoxide, N-A. Pyryl pyrrolidone, acetonitrile or 1,4-dioxane, etc., more preferably tetrahydrofuran.
- a polar aprotic solvent or water preferably tetrahydrofuran (THF), N,N-dimethylformamide, dimethyl sulfoxide, N-A.
- Pyryl pyrrolidone acetonitrile or 1,4-dioxane, etc., more preferably tetrahydrofuran.
- R is preferably tert-butoxycarbonyl (Boc).
- the acid used is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, methanesulfonic acid or trifluoroacetic acid, preferably hydrochloric acid.
- Another aspect of the present application provides an intermediate compound as shown below that can be used to prepare ibu brinib:
- X 1 and X 3 are each independently selected from Cl, Br or I.
- the intermediate compound useful for the preparation of Ibutinib is selected from the group consisting of Structured compound:
- Another aspect of the present application provides the use of an intermediate compound as shown below for the preparation of Ibubutinib:
- X 1 and X 3 are each independently selected from Cl, Br or I.
- the raw materials used are inexpensive and readily available, and only the acylation reaction and the Suzuki reaction are required to obtain ibutinib.
- the method for preparing ibufenib provided by the present application has the following advantages:
- the acylation reaction does not require additional protection of the functional group, and the product yield and purity are high;
- the photo-delay reaction is first carried out to significantly increase the conversion rate of the raw material, and the reaction product can be directly precipitated from the reaction liquid, thereby solving the disadvantage that the product of the photo-delay reaction in the prior art needs to be purified by chromatography.
- the product yield is improved, the purification method is simplified, and the raw material cost is lowered;
- the amount of the catalyst is much lower than that reported in the prior literature, and the conversion of the raw material is 100% after the reaction for 1-5 h. %, a very small amount of impurities generated in the reaction, the product can be purified only by forming the corresponding salt, and the purity of the product is high.
- the compound of the formula 1, the compound of the formula 3 or the compound of the formula 8 may be present in the form of a free base or in the form of a salt with an inorganic or organic acid, all within the scope of the present application. .
- the equivalent means the amount of the substance in terms of molar amount.
- the amount of the compound of Formula 2 described herein is from 0.9 to 2 equivalents relative to the compound of Formula 1, and the molar amount of the compound of Formula 2 is from 0.9 to 2 times the molar amount of the compound of Formula 1.
- the compound of formula 5-Br (20 g, 0.093 mol), the compound of formula 6-Boc (28.21 g, 0.14 mol) and triphenylphosphine (85.79 g, 0.33 mol) were added to anhydrous THF (200 mL) under nitrogen. Medium, light brown suspension. The reaction temperature was lowered to 0 ° C, DIAD (66.14 g, 0.33 mol) was added dropwise, and the temperature was kept below 5 ° C during the dropwise addition. The solution was gradually converted into a pale yellow clear solution, and the temperature was gradually raised to 0-10 ° C while stirring.
- the compound of the formula 1-Br (5 g, 0.017 mol) was dissolved in 2-methyltetrahydrofuran (50 mL) under a nitrogen atmosphere, and a 7% aqueous solution of sodium hydrogen carbonate (2.83 g, 0.034 mol) (40 mL) was added and then cooled.
- a solution of acryloyl chloride (1.52 g, 0.017 mol) in 2-methyltetrahydrofuran (5 mL) was slowly added dropwise to -5 °C. After the dropwise addition, the reaction temperature was kept below 0 ° C while stirring the reaction for 1 h. The reaction mixture was separated and the aqueous layer was evaporated.
- the compound of formula 1-I (5 g, 0.0145 mol) was dissolved in 2-methyltetrahydrofuran (50 mL) under a nitrogen atmosphere, and then 7% aqueous sodium hydrogen carbonate (2.44 g, 0.029 mol) (34.8 mL) The temperature was lowered to -5 ° C, and a solution of acryloyl chloride (1.31 g, 0.0145 mol) in 2-methyltetrahydrofuran (5 mL) was slowly added dropwise, and the reaction temperature was kept below 0 ° C while stirring for 1 h. The reaction mixture was separated and the aqueous layer was evaporated.
- the compound of the formula 1-Br (5 g, 0.017 mol) was dissolved in 2-methyltetrahydrofuran (50 mL) under a nitrogen atmosphere, and a 7% aqueous solution of sodium hydrogen carbonate (2.83 g, 0.034 mol) (40 mL) was added and then cooled. Slowly add 3-chloropropyl to -5 ° C A solution of the acid chloride (2.14 g, 0.017 mol) in 2-methyltetrahydrofuran (5 mL) was taken, and the reaction mixture was kept below 0 ° C and stirred for 1 h. The reaction mixture was separated and the aqueous layer was evaporated.
- the compound of the formula 1-Br (5 g, 0.017 mol) was dissolved in 2-methyltetrahydrofuran (50 mL) under a nitrogen atmosphere, and a 7% aqueous solution of sodium hydrogen carbonate (2.83 g, 0.034 mol) (40 mL) was added and then cooled.
- a solution of 3-bromopropionyl bromide (3.63 g, 0.017 mol) in 2-methyltetrahydrofuran (5 mL) was slowly added dropwise to -5 ° C, and the reaction temperature was kept below 0 ° C while stirring for 1 h. The reaction mixture was separated and the aqueous layer was evaporated.
- EtOAc mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
- the compound of formula 1-I (5 g, 0.0145 mol) was dissolved in 2-methyltetrahydrofuran (50 mL) under nitrogen. Add 7% aqueous solution of sodium hydrogencarbonate (2.44 g, 0.029 mol) (34.8 mL), then cool to -5 ° C, slowly add 3-chloropropanoyl chloride (1.84 g, 0.0145 mol) of 2-methyltetrahydrofuran (5 mL) The solution was centrifuged to maintain the reaction temperature below 0 ° C while stirring for 1 h. The reaction mixture was separated and the aqueous layer was evaporated.
- the compound of formula 1-I (5 g, 0.0145 mol) was dissolved in 2-methyltetrahydrofuran (50 mL) under a nitrogen atmosphere, and then 7% aqueous sodium hydrogen carbonate (2.44 g, 0.029 mol) (34.8 mL) The temperature was lowered to -5 ° C, and a solution of 3-bromopropionyl bromide (3.14 g, 0.0145 mol) in 2-methyltetrahydrofuran (5 mL) was slowly added dropwise, and the reaction temperature was kept below 0 ° C while stirring for 1 h. The reaction mixture was separated and the aqueous layer was evaporated.
- a compound of formula 3-2-Br-Cl (3 g, 7.74 mmol), a compound of formula 4 (2.48 g, 11.61 mmol) and potassium phosphate (5.75 g, 27.09 mmol) were added to 1,4-dioxane (30 mL) After bubbling with nitrogen gas for 20 min in a mixed solvent of water (12 mL), Pd(PPh 3 ) 4 (89.4 mg, 0.077 mmol) was added, and nitrogen gas was bubbled for 5 min, and then the mixture was heated under reflux and stirred for 1 h. Then, the reaction mixture was separated, and the organic layer was evaporated to dryness.
- a compound of formula 3-2-Br-Br (3 g, 6.94 mmol), a compound of formula 4 (2.23 g, 10.41 mmol) and potassium phosphate (5.16 g, 24.3 mmol) were added to 1,4-dioxane (30 mL) After bubbling with nitrogen gas for 20 min in a mixed solvent of water (12 mL), Pd(PPh 3 ) 4 (80.3 mg, 0.069 mmol) was added, and nitrogen gas was bubbled for 5 min, and then the mixture was heated under reflux and stirred for 1 h. Then, the reaction mixture was separated, and the organic layer was evaporated to dryness.
- the dihydrochloride salt of the compound of formula 1-Br (20 g, 0.054 mol), the compound of formula 4 (17.35 g, 0.081 mol) and potassium phosphate (40.15 g, 0.19 mol) were added to 1,4-dioxane (200 mL). And a mixture of water (80 mL), bubbling with nitrogen for 20 min, then adding Pd(PPh 3 ) 4 (0.62 g, 5.4 ⁇ 10 -4 mol), continuing to bubble with nitrogen for 5 min, then heating to reflux The reaction was stirred for 5 h.
- reaction solution was concentrated, and ethyl acetate (100 mL) and water (100 mL) were added to the residue, and the mixture was adjusted to pH 2-3 with hydrochloric acid, and the layers were separated and ethyl acetate (100 mL) Further, methylene chloride (200 mL) was added to the aqueous layer, and the mixture was adjusted to pH 9-10 with 6N sodium hydroxide solution, and the mixture was stirred. The organic layer was dried over anhydrous sodium sulfate and evaporated. It is the free base form of Compound 8, the yield is 90.0%, and the chemical purity is 98.5%. This free base was reacted with a solution of HCl in ethanol to form a salt to obtain 18.9 g of the hydrochloride salt of Compound 8 in a yield of 92% and a chemical purity of 99.1%.
- a compound of formula 1-Br (16.1 g, 0.054 mol), a compound of formula 4 (17.35 g, 0.081 mol) and potassium phosphate (48.5 g, 0.23 mol) were added to ethylene glycol dimethyl ether (200 mL) and water (80 mL). After bubbling with nitrogen gas for 20 min, Pd(PPh 3 ) 4 (0.62 g, 5.4 ⁇ 10 -4 mol) was added, and nitrogen gas was bubbled for 5 min, then heated under reflux and stirred for 5 h.
- reaction solution was concentrated, and ethyl acetate (100 mL) and water (100 mL) were added to the residue, and the mixture was adjusted to pH 2-3 with hydrochloric acid, and the layers were separated and ethyl acetate (100 mL) Further, methylene chloride (200 mL) was added to the aqueous layer, and the mixture was adjusted to pH 9-10 with 6N sodium hydroxide solution, and the mixture was stirred. The organic layer was dried over anhydrous sodium sulfate and evaporated. It is the free base form of Compound 8, the yield is 87.1%, and the chemical purity is 98.8%.
- the dihydrochloride salt of the compound of formula 1-Br (20 g, 0.054 mol), the compound of formula 4 (17.35 g, 0.081 mol) and potassium phosphate (40.15 g, 0.19 mol) were added to DMF (200 mL) and water (80 mL).
- DMF 200 mL
- water 80 mL
- Pd(PhCN) 2 Cl 2 0.21 g, 5.5 ⁇ 10 -4 mol
- reaction solution was concentrated, and ethyl acetate (100 mL) and water (100 mL) were added to the residue, and the mixture was adjusted to pH 2-3 with hydrochloric acid, and the layers were separated and ethyl acetate (100 mL) Further, dichloromethane (200 mL) was added to the aqueous layer, and the mixture was adjusted to pH 9-10 with 6N sodium hydroxide solution, and the mixture was stirred. The organic layer was dried over anhydrous sodium sulfate and evaporated. The yield was 65.1%.
- the dihydrochloride salt of the compound of formula 1-Br (20 g, 0.054 mol), the compound of formula 4 (17.35 g, 0.081 mol) and potassium carbonate (26.14 g, 0.19 mol) were added to 1,4-dioxane (200 mL) And a mixture of water (80 mL), bubbling with nitrogen for 20 min, then adding Pd(PPh 3 ) 4 (0.62 g, 5.4 ⁇ 10 -4 mol), continuing to bubble with nitrogen for 5 min, then heating to reflux The reaction was stirred for 5 h.
- reaction solution was concentrated, and ethyl acetate (100 mL) and water (100 mL) were added to the residue, and the mixture was adjusted to pH 2-3 with hydrochloric acid, and the layers were separated and ethyl acetate (100 mL) Further, dichloromethane (200 mL) was added to the aqueous layer, and the pH was adjusted to 9-10 with 6N sodium hydroxide solution, and the mixture was stirred. The organic layer was dried over anhydrous sodium sulfate and evaporated. The yield was 80.4%.
- the compound of formula 8 (10 g, 0.026 mol) was dissolved in 2-methyltetrahydrofuran (100 mL) under a nitrogen atmosphere, and 7% aqueous sodium bicarbonate (4.37 g, 0.052 mol) (62 mL) was added and then cooled to - A solution of acryloyl chloride (2.34 g, 0.026 mol) in 2-methyltetrahydrofuran (10 mL) was slowly added dropwise at 5 ° C, and the reaction temperature was kept below 0 ° C while stirring for 1 h.
- the reaction mixture was separated, and the aqueous layer was evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
- the hydrochloride salt of the compound of formula 8 (11 g, 0.026 mol) was dissolved in 2-methyltetrahydrofuran (100 mL), and 7% aqueous sodium bicarbonate (5.04 g, 0.06 mol) (72 mL) Then, the temperature was lowered to -5 ° C, and a solution of acryloyl chloride (2.34 g, 0.026 mol) in 2-methyltetrahydrofuran (10 mL) was slowly added dropwise, and the reaction temperature was kept below 0 ° C while stirring for 1 h. The reaction mixture was separated and the aqueous phase was extracted with 2-methyltetrahydrofuran (50 mL).
Abstract
Description
Claims (19)
- 根据权利要求1所述的伊布替尼的制备方法,其中在步骤1中,所述碱为碳酸钾、碳酸钠、碳酸氢钠、碳酸氢钾、氢氧化钠、氢氧化钾、氢化钾、氢化钠、三乙胺、二甲基吡啶、二异丙基乙胺或1,8-二氮杂二环[5.4.0]十一碳-7-烯,优选碳酸氢钠和碳酸氢钾。
- 根据权利要求1所述的伊布替尼的制备方法,其中在步骤1中,反应溶剂选自四氢呋喃,2-甲基四氢呋喃、N,N-二甲基甲酰胺、乙腈或丙酮,优选2-甲基四氢呋喃。
- 根据权利要求1所述的伊布替尼的制备方法,其中在步骤2中,所述催化剂选自Pd(PPh3)4、PdCl2(PPh3)2、PdCl2(PhCN)2、Pd(OAc)2、Pd/C或PdCl2(dppf)2,优选Pd(PPh3)4。
- 根据权利要求1所述的伊布替尼的制备方法,其中在步骤2中,所述碱为碳酸钾、碳酸钠、碳酸铯、醋酸钾、醋酸钠、磷酸钾、磷酸钠、碳酸氢钠、碳酸氢钾、氢氧化钠、氢氧化钾、氢化钠或氢化钾,优选磷酸钾或碳酸钾。
- 根据权利要求1所述的伊布替尼的制备方法,其中在步骤2中,反应溶剂为四氢呋喃、1,4- 二氧六环、乙腈、丙酮、N,N-二甲基甲酰胺、二甲基亚砜、N-甲基吡咯烷酮或乙二醇二甲醚等与水的混合溶剂,优选1,4-二氧六环与水或乙二醇二甲醚与水的混合溶剂。
- 根据权利要求7所述的伊布替尼的制备方法,其中在步骤1中,所述催化剂选自Pd(PPh3)4、PdCl2(PPh3)2、PdCl2(PhCN)2、Pd(OAc)2、Pd/C或PdCl2(dppf)2,优选Pd(PPh3)4。
- 根据权利要求7所述的伊布替尼的制备方法,其中在步骤1中,所述碱为碳酸钾、碳酸钠、碳酸铯、醋酸钾、醋酸钠、磷酸钾、磷酸钠、碳酸氢钠、碳酸氢钾、氢氧化钠、氢氧化钾、氢化钠或氢化钾,优选磷酸钾或碳酸钾。
- 根据权利要求7所述的伊布替尼的制备方法,其中在步骤1中,反应溶剂为四氢呋喃、1,4-二氧六环、乙腈、丙酮、N,N-二甲基甲酰胺、二甲基亚砜、N-甲基吡咯烷酮或乙二醇二甲醚等与水的混合溶剂,优选1,4-二氧六环与水或乙二醇二甲醚与水的混合溶剂。
- 根据权利要求7所述的伊布替尼的制备方法,其中在步骤2中,所述碱为碳酸钾、碳酸钠、碳酸氢钠、碳酸氢钾、氢氧化钠、氢氧化钾、氢化钾、氢化钠、三乙胺、二甲基吡啶、二 异丙基乙胺或1,8-二氮杂二环[5.4.0]十一碳-7-烯,优选碳酸氢钠和碳酸氢钾。
- 根据权利要求7所述的伊布替尼的制备方法,其中在步骤2中,反应溶剂为四氢呋喃,2-甲基四氢呋喃、N,N-二甲基甲酰胺、乙腈或丙酮,优选2-甲基四氢呋喃。
- 根据权利要求13所述的伊布替尼的制备方法,其中所述光延反应试剂由选自三苯基膦、三丁基膦或三甲基膦的第一试剂与由选自偶氮二甲酸二异丙酯、偶氮二甲酸二叔丁酯、偶氮二甲酸二乙酯、偶氮二甲酸二对氯苄酯、1,1’-(偶氮二碳酰)二哌啶、N,N,N’,N’-四异丙基偶氮二羧酰胺、N,N,N’,N’-四甲基偶氮二羧酰胺或4,7-二甲基-3,4,5,6,7,8-六氢-1,2,4,7-四氮杂辛因-3,8-二酮的第二试剂组成,优选地由三苯基膦与偶氮二甲酸二异丙酯组成。
- 根据权利要求13所述的伊布替尼的制备方法,其中用于制备式7化合物的溶剂选自四氢呋喃、N,N-二甲基甲酰胺、二甲亚砜、N-甲基吡咯烷酮、乙腈或1,4-二氧六环,优选四氢呋喃。
- 根据权利要求13所述的伊布替尼的制备方法,其中在式7化合物脱除保护基时所用的酸选自盐酸、氢溴酸、硫酸、磷酸、醋酸、甲磺酸或三氟乙酸,优选盐酸。
- 权利要求17或18所述的中间体化合物在制备伊布替尼中的用途。
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JP2018536640A (ja) * | 2015-10-28 | 2018-12-13 | サイノファーム タイワン,リミティド | イブルチニブ及びその中間体の製造方法 |
JP2020532552A (ja) * | 2017-09-03 | 2020-11-12 | 上海美志医薬科技有限公司Shanghai Meizer Pharmaceuticals Co., Ltd. | ブルトン型チロシンキナーゼBtkの阻害および分解活性を有する化合物 |
CN112824417A (zh) * | 2019-11-21 | 2021-05-21 | 上海天慈国际药业有限公司 | 一种劳拉替尼的制备方法 |
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CN114516830B (zh) * | 2022-02-14 | 2023-12-19 | 兰州优莱特化学科技有限公司 | 利太膦酸的制备方法及应用 |
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