CN115785001A - Preparation method of inflixatanib - Google Patents
Preparation method of inflixatanib Download PDFInfo
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- CN115785001A CN115785001A CN202211477610.1A CN202211477610A CN115785001A CN 115785001 A CN115785001 A CN 115785001A CN 202211477610 A CN202211477610 A CN 202211477610A CN 115785001 A CN115785001 A CN 115785001A
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Abstract
The invention relates to infliximab, in particular to a novel method for preparing infliximab. The method comprises the following steps: 1) Compound I (chemical name: 4, 6-difluoropyrimidine) with methylamine to obtain an intermediate II; 2) Reacting the intermediate II with phenyl chloroformate to obtain an intermediate III; 3) Carrying out substitution reaction on the compound III and the compound IV to obtain an intermediate V; 4) And carrying out substitution reaction on the intermediate V and VI to obtain the final product inflattib. The process route provided by the invention has the advantages that: the method has the advantages of short route, cheap and easily-obtained raw materials, simple and convenient operation, mild conditions, high reaction yield, avoidance of use of highly toxic products, environmental friendliness and easiness in industrial production.
Description
Technical Field
The invention relates to inflatainib, and in particular relates to a novel method for preparing inflatanib.
Background
Infliximab (Infigrtinib) is an orally available selective Fibroblast Growth Factor Receptor (FGFR) tyrosine kinase inhibitor approved by FDA on 29/5/2021 for the treatment of patients with FGFR2 fusion and rearrangement mutations with locally advanced or metastatic cholangiocarcinoma. The chemical name is 3- (2, 6-dichloro-3, 5-dimethoxyphenyl) -1- (6- (4- (4-ethylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -1-methylurea, CAS registry number 872511-34-7, and the structural formula is shown below.
At present, the synthetic route of infliximab is shown as follows, a compound 1 (N-ethylpiperazine) and 4-fluoronitrobenzene undergo substitution reaction to obtain an intermediate 2, and the intermediate IV is obtained through reduction; carrying out substitution reaction on the compound 4 and methylamine to obtain an intermediate 5, and then reacting with a compound IV to obtain an intermediate 6; reacting the compound IV with phosgene to obtain an intermediate 7; the intermediate 6 and 7 react to obtain the final product Infigatinib.
The above technical route has the following defects: the highly toxic triphosgene is used in the synthesis of the intermediate 7, so that the human body and the environment are greatly damaged, and the amplification reaction is not facilitated; the intermediate 7 belongs to isocyanate compounds, urea impurities shown in the specification are easily generated in the preparation process of the intermediate, the solubility of the impurities is poor, the content of Infigatinib is reduced to be below 0.1% only by carrying out repeated recrystallization on the final product, the yield is low, the total yield of the whole route is less than 8%, in addition, the general isocyanates generate interconversion structures due to instability, the compound is generally avoided being generated in the field, and the compound is rarely used as an intermediate.
Disclosure of Invention
In order to overcome the defects of low yield and toxic gas generation in the technical route, the invention provides a new method for synthesizing inflattib, which adopts the following technical route:
the method comprises the following operation steps:
s1 Synthesis of Compound II
Dissolving the compound I in an organic solvent, adding methylamine water solution, then stirring and reacting at 15 ℃, detecting by TLC until the compound I disappears, concentrating under reduced pressure, and filtering to obtain the compound II.
Wherein the organic solvent is one or more of tetrahydrofuran, 1, 4-dioxane, methanol and ethanol, preferably ethanol.
Wherein, the molar ratio of the compound I to the methylamine is 1.8-2.2, preferably, the molar ratio of the compound 1 to the methylamine is 1.
S2: synthesis of Compound III
Dissolving the compound II in an organic solvent, adding phenyl chloroformate within a certain temperature range, then placing the mixture at 25 ℃ for reaction, detecting by TLC until the compound II disappears, adding water into the reaction liquid, performing liquid separation and extraction, drying an organic layer by using anhydrous sodium sulfate, performing suction filtration, and removing the solvent under reduced pressure to obtain the compound III.
Wherein the organic solvent is one or more of dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, acetonitrile, acetone and toluene, preferably dichloromethane.
Wherein the molar ratio of the compound III to the phenyl chloroformate is 1-2; preferably, the molar ratio of the compound III to the phenyl chloroformate is 1.
Wherein the temperature for adding the phenyl chloroformate is-10 to 10 ℃, preferably-5 to 5 ℃.
S3: synthesis of Compound V
Dissolving a compound III in an organic solvent, adding a proper alkali at 0 ℃, dissolving a compound IV in the organic solvent, dropwise adding the compound IV into the compound III, stirring the mixture at 25 ℃ for reaction, detecting by TLC until the compound III disappears, removing the solvent under reduced pressure, adding dichloromethane and water, performing liquid separation extraction, drying an organic layer by using anhydrous sodium sulfate, performing suction filtration, removing the solvent under reduced pressure, and recrystallizing by using ethanol to obtain a pure product of the compound V.
Wherein the organic solvent is one or more of dichloromethane, tetrahydrofuran, N-dimethylformamide, N-methylpyrrolidone and dimethyl sulfoxide, and tetrahydrofuran is preferred.
Wherein the base is one or more of triethylamine, N-diisopropylethylenediamine, pyridine and 4-dimethylaminopyridine, and triethylamine is preferred.
Wherein, the molar ratio of the compound III, the alkali and the compound IV is 1-1.5.
S4: synthesis of infliximab
Dissolving a compound VI in an organic solvent, adding a proper alkali at 0 ℃, stirring for 30min, dissolving a compound V in the organic solvent, dropwise adding the compound V into a compound III, stirring for reaction at 25 ℃, detecting by TLC until the compound V disappears, cooling the system temperature to 0 ℃, adding water, continuously stirring for 1h, carrying out suction filtration, and recrystallizing a filter cake by N, N-dimethylformamide to obtain the pure inflixorab.
Wherein the organic solvent is one or more of tetrahydrofuran, 1, 4-dioxane and N, N-dimethylformamide, and preferably N, N-dimethylformamide.
Wherein the alkali is one or more of potassium tert-butoxide, sodium hydrogen and lithium bis (trimethylsilyl) amide, and sodium hydrogen is preferred.
Wherein, the molar ratio of the compound V, the alkali and the compound VI is 1.5-2.2.
Advantageous effects
1. The invention is different from the prior art in the starting raw materials and the reaction sequence is adjusted, and is one of the key points of the invention, specifically, the invention firstly uses the compound I to react with methylamine to generate the compound II, uses phenyl chloroformate to react with the compound II to form the compound III, reacts with the compound IV to obtain the compound V, and reacts with the compound VI to obtain the final product; whereas the prior art is the reaction of compound 5 with compound VI to form compound 6, the reaction of compounds 6 and 7 to form the final product. The invention selects the starting raw materials with higher activity, adjusts the reaction sequence to be different, has the total yield of 69.7 percent, the purity of more than 99 percent, is far higher than the total yield (less than 8 percent) of the prior art route, has the purity of more than 99 percent, produces unexpected technical effect, and is very suitable for industrial production.
2. The invention provides a new method for inflixatanib, which avoids the use of highly toxic phosgene, greatly reduces the harm to human bodies and the environment, simultaneously avoids the generation of impurities which are difficult to remove by a new route, and reduces the purification cost.
3. In the step of synthesizing the crude product of inflatainib, the method adopts milder conditions to replace high temperature due to higher substrate activity, replaces difficult-to-recover acetic acid with easily-recovered solvent, and is more convenient in process. The method comprises the following specific steps: in the prior art, high-temperature reflux (140 ℃ reflux) is required during the reaction of the compounds 6 and 7, but the reaction at room temperature is adopted, so that the reaction requirement is greatly reduced.
Drawings
FIG. 1 is a graph of hydrogen spectra obtained for Infogratinib according to the present invention;
FIG. 2 is a carbon spectrum of inflatanib obtained by the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the following embodiments further describe the present invention in detail. The experimental methods in the present invention are all conventional methods unless otherwise specified. It should be understood that the specific embodiments described herein are merely illustrative of the invention and do not limit the invention.
The progress of the reaction of the present invention can be monitored by conventional monitoring methods in the art (e.g., TLC, HPLC or NMR), typically at the end of the reaction when starting material is lost.
The compounds I, IV and VI of the present invention are available from Shanghai Bide pharmaceutical science and technology, inc., and other chemical reagents and raw materials are available from Saen chemical technology, inc.
Example 1:
the preparation method specifically comprises the following steps:
dissolving a compound I (150g, 1.3 mol) in ethanol (1.5L), adding a methylamine aqueous solution (532mL, 2.6 mol) with the mass fraction of 20%, stirring and reacting at 15 ℃ for 6h, detecting the disappearance of the compound I by TLC, removing the ethanol under reduced pressure, and performing suction filtration to obtain a compound II;
the method is adopted to prepare 151g of light yellow solid with the yield of 91.9%.
The intermediate II prepared in this example was identified with the following results:
ESI-MS(m/z):128.13；
1 H NMR(400MHz,CDCl 3 )δ8.12(d,J＝1.3Hz,1H),6.32(dd,J＝6.3,1.2Hz,1H),2.82(d,J＝4.6Hz,3H).
example 2:
embodiment 2 of the present invention provides a preparation method of an intermediate III, and the synthetic route thereof is as follows:
the preparation method specifically comprises the following steps:
compound II (140g, 1.1 mol) was dissolved in methylene chloride (1.5L), phenyl chloroformate (152mL, 1.2 mol) was added at-5 ℃ followed by reaction at 25 ℃ for 1h, disappearance of Compound II was detected by TLC, water (0.6L) was added to the reaction solution, extraction was carried out by liquid separation, the organic layer was dried over anhydrous sodium sulfate, suction filtration was carried out, and the solvent was removed under reduced pressure to obtain Compound III.
The method is adopted to obtain 269g of light yellow solid with the yield of 98.8%.
The identification of intermediate III prepared in this example gave the following results:
ESI-MS(m/z):248.21；
1 H NMR(400MHz,CDCl 3 )δ8.32(d,J＝1.3Hz,1H),7.59–7.32(m,3H),7.24–7.15(m,3H),3.60(s,3H).
example 3:
embodiment 3 of the present invention provides a preparation method of intermediate V:
compound III (135g, 0.55mol) was dissolved in tetrahydrofuran (1.0L), triethylamine (83.5 mL, 0.60mol) was added at 0 ℃, compound IV (121g, 0.55mol) was dissolved in tetrahydrofuran (0.8L), and the solution was added dropwise to compound III, followed by reaction at 25 ℃ for 18h, disappearance of compound III was detected by TLC, the solvent was removed under reduced pressure, dichloromethane (1.5L) and water (1.0L) were added, liquid-separation extraction was performed, the organic layer was dried with anhydrous sodium sulfate, suction filtration was performed, the solvent was removed under reduced pressure, and recrystallization from ethanol (2.1L) gave a pure product of compound V.
182g of white solid is obtained by the method, and the yield is 88.8%.
The identification of intermediate III prepared in this example gave the following results:
ESI-MS(m/z):376.16；
1 H NMR(400MHz,CDCl 3 )δ8.24(d,J＝1.3Hz,1H),7.89(s,1H),6.70(dd,J＝8.0,1.4Hz,1H),6.39(s,1H),3.85(s,6H),3.63(s,3H).
example 4:
embodiment 4 of the present invention provides a method for preparing intermediate V:
compound III (120g, 0.49mol) was dissolved in tetrahydrofuran (0.9L), N-diisopropylethylamine (93mL, 0.53mol) was added at 0 ℃, compound IV (108g, 0.49mol) was dissolved in tetrahydrofuran (0.6L), added dropwise to Compound III, followed by reaction at 25 ℃ for 18h, detection of disappearance of Compound III by TLC, removal of the solvent under reduced pressure, addition of dichloromethane (1.2L) and water (0.9L), liquid-separation extraction, drying of the organic layer using anhydrous sodium sulfate, suction filtration, removal of the solvent under reduced pressure, recrystallization from ethanol (1.9L) to give pure Compound V. .
154g of white solid was obtained by the method with a yield of 84.6%.
Example 5:
embodiment 5 of the present invention provides a method for preparing infliximab, wherein the synthetic route is as follows:
the preparation method specifically comprises the following steps:
dissolving a compound VI (60g, 0.29mol) in N, N-dimethylformamide (0.4L), adding sodium hydrogen (60%, 23g and 0.58mol) at 0 ℃, stirring for 30min, dissolving a compound V (110g, 0.29mol) in N, N-dimethylformamide (0.8L), dropwise adding the mixture into a compound III, then stirring and reacting at 25 ℃ for 1693 h, detecting the disappearance of the compound V by TLC, cooling the system temperature to 0 ℃, adding water (2.0L), continuously stirring for 1h, carrying out suction filtration, and recrystallizing a filter cake by N, N-dimethylformamide (0.8L) to obtain a pure product of inflixatinib.
142g of white solid is obtained by the method, the yield is 86.4%, and the purity is 99.8%.
The identification of inflixatanib prepared in this example gave the following results:
ESI-MS(m/z):561.42；
1 H NMR(400MHz,DMSO-d 6 )δ12.08(s,1H),9.44(s,1H),8.39(s,1H),7.41(d,J＝8.4Hz,2H),6.90(m,3H),6.41(s,1H)，3.94(s,6H)，3.36-3.33(m,4H),3.31(s,3H),3.09(m,4H),2.38(q,J＝7.3Hz,2H),1.04(t,J＝7.2Hz,3H).
13 C NMR(101MHz,DMSO-d 6 )δ162.23,159.67,156.36，154.71,153.33,135.03,122.52,116.30,113.10,97.12,90.18,57.19,52.82,52.09,49.08,32.18,12.43.
example 6:
embodiment 6 of the present invention provides a method for preparing inflattib:
dissolving a compound VI (55g, 0.27mol) in N, N-dimethylformamide (0.35L), adding potassium tert-butoxide (60g, 0.54mol) at 0 ℃, stirring for 30min, dissolving a compound V (100g, 0.29mol) in N, N-dimethylformamide (0.7L), dropwise adding into the compound III, then stirring for reaction at 25 ℃ for 24h, detecting by TLC until the compound V disappears, cooling the system temperature to 0 ℃, adding water (2.0L), continuously stirring for 1h, performing suction filtration, and recrystallizing a filter cake by N, N-dimethylformamide (0.75L) to obtain the pure product of inflixoratinib.
120g of white solid is obtained by the method, the yield is 80.3%, and the purity is 99.8%.
Example 7:
embodiment 7 of the present invention provides a method for preparing inflatanib:
dissolving a compound VI (44g, 0.21mol) in N, N-dimethylformamide (0.45L), adding a (tetrahydrofuran solution, 1mol/L,0.43L, 0.42mol) of lithium bistrimethylsilyl amide at 0 ℃, stirring for 30min, dissolving a compound V (80g, 0.21mol) in N, N-dimethylformamide (0.55L), dropwise adding the compound into a compound III, stirring at 25 ℃ for reaction for 18h, detecting by TLC until the compound V disappears, reducing the system temperature to 0 ℃, adding water (2.0L), continuously stirring for 1h, performing suction filtration, and recrystallizing a filter cake by N, N-dimethylformamide (0.65L) to obtain a pure product of inflixatanib.
101g of white solid obtained by the method has the yield of 84.5 percent and the purity of 99.7 percent.
Example 8:
embodiment 8 of the present invention provides a method for preparing inflatanib:
dissolving a compound VI (11g, 53.3mmol) in tetrahydrofuran (50 mL), adding a solution of lithium bistrimethylsilyl amide (1 mol/L,106mL, 106mmol) at 0 ℃, stirring for 30min, dissolving a compound V (20g, 53.3mmol) in tetrahydrofuran (150 mL), dropwise adding the solution into a compound III, stirring at 25 ℃ for 22h, detecting by TLC until the compound V disappears, reducing the system temperature to 0 ℃, adding water (2.0L), continuously stirring for 1h, performing suction filtration, and recrystallizing a filter cake by N, N-dimethylformamide (160 mL) to obtain a pure product of inflixoratinib.
The yield of the white solid obtained by the method is 80.3 percent, and the purity is 99.8 percent.
The above-described embodiments of the present invention should not be construed as limiting the scope of the present invention. Any other corresponding changes and modifications made according to the technical idea of the present invention should be included in the protection scope of the claims of the present invention.
Claims (5)
1. A novel synthesis method of infliximab is characterized by comprising the following steps:
the method comprises the following operation steps:
s1 Synthesis of Compound II
Dissolving a compound I in an organic solvent, adding a methylamine water solution, then stirring and reacting at 15 ℃, detecting by TLC until the compound I disappears, concentrating under reduced pressure, and performing suction filtration to obtain a compound II;
s2: synthesis of Compound III
Dissolving a compound II in an organic solvent, adding phenyl chloroformate within a set temperature range, then placing the mixture at 25 ℃ for reaction, detecting by TLC until the compound II disappears, adding water into the reaction solution, performing liquid separation and extraction, drying an organic layer by using anhydrous sodium sulfate, performing suction filtration, and removing the solvent under reduced pressure to obtain a compound III;
s3: synthesis of Compound V
Dissolving a compound III in an organic solvent, adding alkali at 0 ℃, dissolving a compound IV in the organic solvent, dropwise adding the compound IV into the compound III, stirring and reacting at 25 ℃, detecting by TLC until the compound III disappears, removing the solvent under reduced pressure, adding dichloromethane and water, performing liquid separation and extraction, drying an organic layer by using anhydrous sodium sulfate, performing suction filtration, removing the solvent under reduced pressure, and recrystallizing by using ethanol to obtain a pure product of the compound V;
s4: synthesis of infliximab
Dissolving a compound VI in an organic solvent, adding alkali at 0 ℃, stirring for 30min, dissolving a compound V in the organic solvent, dropwise adding the mixture into a compound III, stirring for reaction at 25 ℃, detecting by TLC until the compound V disappears, cooling the system temperature to 0 ℃, adding water, continuously stirring for 1h, carrying out suction filtration, and recrystallizing a filter cake by N, N-dimethylformamide to obtain a pure product of inflixorab.
2. The method for synthesizing inflixatanib as claimed in claim 1, wherein the organic solvent used in the synthesis of the compound II in step S1 is one or more of tetrahydrofuran, 1, 4-dioxane, methanol and ethanol; the molar ratio of the compound I to the methylamine is 1.8-2.2.
3. The method for synthesizing inflixatanib as claimed in claim 1, wherein the organic solvent used in the synthesis of the compound III in step S2 is one or more of dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, acetonitrile, acetone and toluene; the molar ratio of the compound III to the phenyl chloroformate is 1-2; the temperature for adding the phenyl chloroformate is-10 to 10 ℃.
4. The method for synthesizing inflatainib according to claim 1, wherein the organic solvent used in the synthesis of compound V in step S3 is one or more of dichloromethane, tetrahydrofuran, N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide; the alkali used in the synthesis of the compound V in the step S3 is one or more of triethylamine, N-diisopropylethylenediamine, pyridine and 4-dimethylaminopyridine; the molar ratio of the compound III, the base and the compound IV is 1-1.5.
5. The method for synthesizing inflatainib as claimed in claim 1, wherein the step S4 is performed by using one or more organic solvents selected from tetrahydrofuran, 1, 4-dioxane and N, N-dimethylformamide as an organic solvent; the alkali used in the synthesis of the compound V in the step S4 is one or more of potassium tert-butoxide, sodium hydrogen and bis-trimethylsilyl amido lithium; the molar ratio of the compound V, the base and the compound VI is 1.5-2.2.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101035769A (en) * | 2004-06-24 | 2007-09-12 | 诺瓦提斯公司 | Pyrimidine urea derivatives as kinase inhibitors |
| CN102639510A (en) * | 2009-12-07 | 2012-08-15 | 诺瓦提斯公司 | Crystalline forms of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea and salts thereof |
| CN114207151A (en) * | 2019-05-31 | 2022-03-18 | Qed医药股份有限公司 | Method for treating cancer of urinary system |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101035769A (en) * | 2004-06-24 | 2007-09-12 | 诺瓦提斯公司 | Pyrimidine urea derivatives as kinase inhibitors |
| CN102639510A (en) * | 2009-12-07 | 2012-08-15 | 诺瓦提斯公司 | Crystalline forms of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea and salts thereof |
| CN105061332A (en) * | 2009-12-07 | 2015-11-18 | 诺华股份有限公司 | Crystalline forms of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea and salts thereof |
| CN114207151A (en) * | 2019-05-31 | 2022-03-18 | Qed医药股份有限公司 | Method for treating cancer of urinary system |
Non-Patent Citations (1)
| Title |
|---|
| VITO GUAGNANO等: "Discovery of 3-(2, 6-Dichloro-3, 5-dimethoxy-phenyl)-1- {6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}- 1-methyl-urea (NVP-BGJ398), A Potent and Selective Inhibitor of the Fibroblast Growth Factor Receptor Family of Receptor Tyrosine Kinase", J. MED. CHEM., vol. 54, pages 7066 - 7083, XP002689272, DOI: 10.1021/jm2006222 * |
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