CN101885698B - Pyrrolyl acrylamide compound and application thereof to synthesis of sunitinib - Google Patents
Pyrrolyl acrylamide compound and application thereof to synthesis of sunitinib Download PDFInfo
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- CN101885698B CN101885698B CN2009101431494A CN200910143149A CN101885698B CN 101885698 B CN101885698 B CN 101885698B CN 2009101431494 A CN2009101431494 A CN 2009101431494A CN 200910143149 A CN200910143149 A CN 200910143149A CN 101885698 B CN101885698 B CN 101885698B
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- WINHZLLDWRZWRT-ATVHPVEESA-N CCN(CC)CCNC(c1c(C)[nH]c(/C=C(/c2cc(F)ccc2N2)\C2=O)c1C)=O Chemical compound CCN(CC)CCNC(c1c(C)[nH]c(/C=C(/c2cc(F)ccc2N2)\C2=O)c1C)=O WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 1
- IFEUMNNXFOJBCK-MDZDMXLPSA-N CCN(CC)CCNC(c1c(C)[nH]c(/C=C/C(Nc(ccc(F)c2)c2Cl)=O)c1C)=O Chemical compound CCN(CC)CCNC(c1c(C)[nH]c(/C=C/C(Nc(ccc(F)c2)c2Cl)=O)c1C)=O IFEUMNNXFOJBCK-MDZDMXLPSA-N 0.000 description 1
Abstract
The invention discloses a precursor compound of sunitinib, i.e. a pyrrolyl acrylamide compound, a preparation method thereof, and a new method for preparing sunitinib using the compound. The chemical name of the compound is N-[2-(diethylamino) ethyl]-5[-(E)-2-(4-fluorine-2-halogenated-carbaniloyl)-vinyl]-2,4-dimethyl-1H-pyrro-3-formamide. The compound can be conveniently prepared into sunitinib in high yield through intramolecular Heck reaction.
Description
Technical field
What the present invention relates to is a kind of precursor compound of Sutent---pyrrolyl acrylamide compound, the preparation method of this compound, and the novel method of this compound Sutent of a kind of usefulness.
Background technology
Sutent (sunitinib; I) be a kind of many target spots tyrosine kinase inhibitor with highly selective; Chemical name be N-[2-(diethylin) ethyl]-5-[(Z)-5-fluoro-1; 2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl--1H-pyrrole-3-carboxamide, chemical structure is suc as formula shown in (I):
WO 01/45689, US 6; 316; 429, US 7; 119,209, WO 01/60814 etc. and J.Med.Chem.2003:1116-1119, Bioorganic & Medicinal Chemistry Letters 2005:4380-4384, J.Org.Chem., 2003:6447-6450 etc. have reported the compound method of Sutent.
The compound method of above Sutent; All be with 5-fluoro-1; 3-Indolin-2-one (II) is a raw material, and with 2,4-dimethyl--5-formyl radical-1H-pyrroles-3-carboxylic acid derivative (A) or its analogue are through condensation reaction (Knoevenagel condensation); Obtain through necessary conversion, reaction process is shown in reaction formula (1) again:
Reaction formula (1):
In the above-mentioned reaction formula, 5-fluoro-1,3-Indolin-2-one (II) preparation method; According to prior art such as J.Chem.Educ.1993,70 (4): 332, Pharmazie, 1958; 23:1858-1861, WO 2001060814 are said, need to use a large amount of dangerous Hydrazine Hydrate 80 (NH
2NH
2.H
2Raw material such as O), the dark by product aftertreatment difficulty of the spent acid of preparation process and generation, environmental pollution is big.Reaction process is shown in reaction formula (2):
Reaction formula (2):
Especially, in the said reaction process of reaction formula (2), hydrazine hydrate reduction reaction (Wolff-Kishner reaction) needs with excessive even excessive greatly Hydrazine Hydrate 80 to improve reaction yield, the very big danger of existence in the production process.So, study the compound method of new Sutent, avoid the use of 5-fluoro-1,3-Indolin-2-one (II) is a raw material, the danger that fundamentally overcomes in the production process is necessary and significant.
Summary of the invention
The precursor compound that the purpose of this invention is to provide a kind of Sutent precursor---pyrrolyl acrylamide compound.Another object of the present invention has provided the preparation method of this pyrrolyl acrylamide compound, the purposes of this compound in the preparation Sutent.Another object of the present invention provides a kind of method for preparing Sutent of novelty.
The substituted acrylamides of pyrryl of the present invention; Chemical name is N-[2-(diethylin) ethyl]-5-[(E)-2-(4-fluoro-2-halo-carbaniloyl,phenylcarbamoyl)-vinyl]-2; 4-dimethyl--1H-pyrrole-3-carboxamide, structure is suc as formula shown in (III):
X in above-mentioned (III) formula structure is haloid element Cl, Br or I.
Among the present invention; The preparation of the substituted acrylamides of pyrryl (III); Can be by corresponding [(4-fluoro-2-halo-carbaniloyl,phenylcarbamoyl)-methyl]-diethyl phosphonate (IV) and N-(2-diethylin ethyl)-2; 4-dimethyl--5-formyl radical-1H-pyrrole-3-carboxamide (V) obtains through Horner-Emmons-Wittig reaction (HEW reaction) condensation, and reaction process is shown in reaction formula (3):
Reaction formula (3):
X in the above-mentioned reaction formula (3) is haloid element Cl, Br or I; R is methyl or ethyl.
Above-mentioned Horner-Emmons-Wittig reaction in a kind of polar aprotic solvent, is carried out under the alkaline condition usually.Specifically, in the mixture of compound (IV), compound (V) and solvent, behind the adding alkali, stirring reaction liquid is accomplished.The example of the polar aprotic solvent that uses in the reaction is an ether solvents, THF, 1 for example, 4-dioxane; Nitrile solvent, for example acetonitrile; And amide solvent, N for example, dinethylformamide, DMAC N,N.Reaction solvent is acetonitrile or N preferably, dinethylformamide.The example that reacts used alkali is a tertiary amine, for example 1, and 8-diazabicyclo [5.4.0] 11 carbon-7-alkene (DBU); Alkali metal hydroxide is like sodium hydroxide, Lithium Hydroxide MonoHydrate, Pottasium Hydroxide; And alkaline carbonate, like cesium carbonate, salt of wormwood.Reacting preferred alkali is Lithium Hydroxide MonoHydrate or Pottasium Hydroxide.
The temperature of reaction of above-mentioned reaction can be in quite wide in range scope, and precise dose is unimportant to this reaction, is generally 0 ℃ of reflux temperature to solvent.
According to the present invention, above-mentioned reaction need not the pure article that further crystallization purifying obtains compound (III) after finishing.Reaction gained crude product promptly can be used for step reaction down with the preparation Sutent.Specifically, after above-mentioned Horner-Emmons-Wittig reaction was accomplished, the resistates that reacting liquid filtering concentrates the back gained can directly be used for the synthetic of Sutent.In addition, this resistates also can further be handled, and for example, adds entry, uses organic solvent extraction, remove water-soluble substances after, merge organic phase after, dry precipitation is used further to the synthetic of Sutent.
The described compound of above-mentioned preparation process (IV); Can be with reference to relevant document; Like Org.Biomol.Chem.2004; The similar method of 2:3427-3431 obtains midbody (VII) by corresponding 4-fluoro-2-halo-aniline (VI) and chloroacetyl chloride condensation, and then obtains with trimethyl phosphite or triethyl-phosphite reaction.Reaction process is shown in reaction formula (4):
Reaction formula (4):
Likewise, the X in the above-mentioned reaction formula (4) is haloid element Cl, Br or I; R is methyl or ethyl.
The said compound of above-mentioned preparation process (V) can be through those methods well known in the art, for example, and Chinese Journal of Pharmaceuticals 2007,38:539-541, Org.Prep.Proced.Int.1981,13:97-102 preparation.
According to the present invention, the substituted acrylamides of the pyrryl of above-mentioned form (III) can pass through intramolecular ring-closure reaction, preparation medicinal compound---Sutent, and reaction process is shown in reaction formula (5):
Reaction formula (5):
Wherein, X is Cl, Br or I.
Above-mentioned ring-closure reaction is a kind of intramolecular Heck linked reaction.Specifically, pyrrolyl acrylamide compound (III) combination reaction of under the condition that catalyzer that the Heck linked reaction is allowed and weak base exist, carrying out.Though those skilled in the art know this reaction and can in the presence of multiple transition-metal catalyst, carry out that the catalyzer that the present invention recommends to use is the palladium compounds.Can be used as preferred palladium compounds and comprise Palladous chloride, palladium, two (triphenylphosphine) palladium chloride (II), palladium-triphenylphosphine etc.
Alkali in this reaction is selected from aliphatic tertiary amine, as 1, and 8-diazabicyclo [5.4.0] 11 carbon-7-alkene, triethylamine; Alkaline carbonate such as cesium carbonate, salt of wormwood.
Above-mentioned reaction is preferably carried out in a kind of polar aprotic solvent usually.The suitable solvent has: ethers, and like THF, 1, the 4-dioxane; Nitrile is like acetonitrile; And amides, like N, N,N-DIMETHYLACETAMIDE etc.Reaction solvent is preferably nitrile, amides.
Temperature of reaction is relevant with selected solvent and alkali, selects different solvent, alkali, and temperature of reaction is different, 35 ℃ to 120 ℃ of preferred temperature.
According to the present invention, it is characterized in that in the preparation process of above-mentioned Sutent, the used raw material of intramolecular Heck linked reaction can also use the said reaction solution of reaction formula (3) directly to carry out.Concretely; After the said reaction of reaction formula (3) is accomplished; Reaction solution is after simple filtering, concentrate etc. is operated; Can under above-mentioned Heck coupling condition, carry out the prepared in reaction Sutent by the gained enriched material, and need not to obtain the pure article of compound (III), help suitability for industrialized production through complicated procedures of forming such as crystallization, dryings.
When adopting the substituted acrylamides of above-mentioned pyrryl of the present invention (III) preparation Sutent; Compare with the related manufacturing processes that known references is reported; A significant advantage is to avoid the use of 5-fluoro-1; 3-Indolin-2-one (II) is a raw material, thereby the raw materials such as Hydrazine Hydrate 80 of the danger of needing in the relative production process having avoided have solved a large amount of spent acid of preparation process and the dark by product aftertreatment problem of generation.Another advantage of the present invention is; One step cyclization makes up the indolone structure of Sutent; Avoided 5-fluoro-1, the indole ketone by product of the generation in 3-Indolin-2-one (II) building-up process, and these by products are more hard to manage; And influence the purity of midbody, and finally influence final product---the purity of Sutent.
According to foregoing, under the prerequisite that does not break away from the above-mentioned basic fundamental thought of the present invention,, modification, replacement or the change of various ways can also be arranged to above-mentioned content according to the ordinary skill knowledge and the customary means of this area.
Through the embodiment of embodiment form, foregoing of the present invention is remake further detailed description below.But should this be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following instance.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
The test condition of HPLC:
Chromatographic column: Prodigy (Phenomenex) 5 μ m C-18 column, 4.6 * 250mm;
Moving phase: CH
3CN/MeOH/20mM, pH 6.7 KHPO
4 -(volume ratio 3: 1: 1);
Flow velocity: 1.5mL/min;
Detector: UV-detector, wavelength 240nm.
Embodiment
Instance 1.2-chloro-N-(4-fluoro-2-iodo-phenyl)-ethanamide (VII-A)
Drying tube is being housed, TM, in the 250mL four-hole bottle of tap funnel and mechanical stirring slurry, adding 4-fluoro-2-iodo-aniline (15.0g, 0.63mol), diisopropylethylamine (8.4g, 0.65mol), and methylene dichloride (100mL), stirring and dissolving, cooling.Under-10～0 ℃, (7.3g, methylene dichloride 0.64mol) (30mL) solution finishes, naturally intensification and transform fully in room temperature reaction to raw material to drip chloroacetyl chloride.Use 2 * 80mL saturated brine and 80mL deionized water wash successively, organic phase is used anhydrous sodium sulfate drying.Filter, methylene dichloride is sloughed in decompression.Resistates is used ethyl alcohol recrystallization, after the vacuum-drying, gets faint yellow plate crystal 18.1g, yield 91.8%.Fusing point: 106.6-107.7 ℃; C
8H
6ClFINO, ESI-MS m/z: [M-H]
-312.32;
1H NMR (CDCl
3, 400MHz) 8.62 (br, 1H), 8.18-8.146 (m, 1H), 7.55-7.53 (m, 1H), 7.13-7.09 (m, 1H), 4.23 (s, 2H) ppm;
13C NMR (CDCl
3, 100MHz) 164.1,160.3 (d, J
C-F=248.4Hz), 133.9,125.9 (d, J
C-F=24.8Hz), 122.7 (d, J
C-F=7.9Hz), 116.2 (d, J
C-F=21.7Hz), 89.6 (d, J
C-F=8.2Hz), 43.1ppm.
The preparation of instance 2. [(4-fluoro-2-iodo-carbaniloyl,phenylcarbamoyl)-methyl]-diethyl phosphonate (IV-A)
Reflux condensing tube is being housed, TM, in the 100mL there-necked flask of nitrogen ingress pipe, add successively 2-chloro-N-(4-fluoro-2-iodo-phenyl)-ethanamide (VII-A) (11.1g, 35.4mmol), triethyl-phosphite (6.1g, 36.5mmol).Under the nitrogen protection, about 16 hours, TLC shows that raw material disappears basically in 130～140 ℃ of following stirring reactions.After the cooling, the reactant of gained is used re-crystallizing in ethyl acetate, after the vacuum-drying, gets white, needle-shaped crystals 13.6g yield 92.6%.Fusing point: 89.1-90.6 ℃; C
12H
16FINO
4P, ESI-MS m/z: [M+H]
+416.04;
1H NMR (400MHz, DMSO-d6) 9.51 (s, 1H), 7.78-7.75 (m, 1H), 7.47-7.43 (m, 1H), 7.30-7.25 (m, 1H), 4.13-4.05 (m, 4H), 3.20 (d, J=21Hz, 2H), 1.25 (t, J=8.0Hz, 3H) ppm;
13C NMR (100MHz, DMSO-d6) 164.0,160.8 (d, J
C-F=246Hz), 136.5 (d, J
C-F=5.7Hz), 128.1 (d, J
C-F=8.4Hz), 125.9 (d, J
C-F=24.1Hz), 116.1 (d, J
C-F=22Hz), 96.0 (d, J
C-F=8.1Hz), 62.3 (d, J
C-P=9.1Hz), and 36.1,34.7,16.8,16.7ppm.
The preparation of instance 3. [(4-fluoro-2-bromo-carbaniloyl,phenylcarbamoyl)-methyl]-diethyl phosphonate (IV-B)
According to the method for instance 2, (4-fluoro-2-bromo-phenyl)-ethanamide is feedstock production target compound (IV-B) with 2-chloro-N-, yield 93.6%.Fusing point: 112-114 ℃; C
12H
16BrFNO
4P, ESI-MS m/z: [M+H]
+369.04;
1H NMR (400MHz, CDCl
3)=9.96 (br, 1H), 7.70-7.68 (m, 1H), 7.36-7.32 (m, 1H), 6.85 (t, J=8.4Hz, 1H), 4.28-4.20 (m, 4H), 3.08 (d, J=21.8Hz, 2H), 1.41 (t, J=7.0Hz, 6H);
13C NMR (100MHz, CDCl
3)=162.2 (d, J
C-P=4.7Hz), 155.5 (d, J
C-F=242.8Hz), 135.3 (d, J
C-F=3.0Hz), 123.9,119.5 (d, J
C-F=6.7Hz), 116.0 (d, J
C-F=23.1Hz), 108.6 (d, J
C-F=21.7Hz), 63.3 (d, J
C-P=6.7Hz), 37.0 (d, J
C-P=128.9Hz), 16.4 (d, J
C-P=6.1Hz).
The preparation of instance 4. [(4-fluoro-2-chloro-carbaniloyl,phenylcarbamoyl)-methyl]-diethyl phosphonate (IV-C)
According to the method for instance 2, (4-fluoro-2-chloro-phenyl)-ethanamide is feedstock production target compound (IV-C) with 2-chloro-N-, yield 95.6%.Fusing point: 102-104 ℃; C
12H
16ClFNO
4P, ESI-MS m/z: [M+H]
+324.6;
1H NMR (400MHz, CDCl
3)=9.94 (br, 1H), 7.58-7.56 (m, 1H), 7.28-7.24 (m, 1H), 6.87 (t, J=8.8Hz, 1H), 4.27-4.20 (m, 4H), 3.07 (d, J=21.7Hz, 2H), 1.41 (t, J=7.0Hz, 6H);
13C NMR (100MHz, CDCl
3)=162.3 (d, J
C-P=4.7Hz), 155.5 (d, J
C-F=244.1Hz), 135.0 (d, J
C-F=3.2Hz), 121.2,120.8 (d, J
C-F=23.2Hz) 118.7 (d, J
C-F=6.7Hz), 116.1 (d, J
C-F=21.8Hz), 63.3 (d, J
C-P=6.6Hz), 37.0 (d, J
C-P=128.9Hz), 16.4 (d, J
C-P=6.2Hz).
Instance 5.N-[2-(diethylin) ethyl]-5-[(E)-and 2-(4-fluoro-2-iodo-carbaniloyl,phenylcarbamoyl)-vinyl]-2, the preparation of 4-dimethyl--1H-pyrrole-3-carboxamide (III-A)
Reflux condensing tube is being housed, and TM is in the 250mL there-necked flask of nitrogen ingress pipe; Add [(4-fluoro-2-iodo-carbaniloyl,phenylcarbamoyl)-methyl]-diethyl phosphonate (IV-A) (25.0g successively; 60.2mmol), N-(2-diethylin ethyl)-2,4-dimethyl--5-formyl radical-1H-pyrrole-3-carboxamide (V) (with reference to Org.Prep.Proced.Int.1981,13:97-102 preparation) (16.0g; 60.2mmol), Lithium Hydroxide MonoHydrate (2.2g, 90.3mmol) and N (100mL).Under the nitrogen protection, about 10 hours, TLC shows that raw material disappears basically in 100 ℃ of stirring reactions.After decompression and solvent recovery N, resistates add methylene dichloride 300mL dissolving, use successively saturated aqueous common salt (2 * 100mL), deionized water (100mL) washing, organic phase is used anhydrous Na
2SO
4Drying is filtered, and concentrating under reduced pressure gets oily matter 32.1g, and this oily matter can directly be used for going on foot down synthetic.This oily matter is used the acetonitrile recrystallization, after the vacuum-drying, gets faint yellow plate crystal 24.1g, yield 76.1%.Fusing point: 68.6-70.6 ℃; C
22H
28FIN
4O
2, ESI-MS m/z: [M+H]
+527.40;
1H NMR (DMSO-d6,400MHz) 11.31 (s, 1H), 9.28 (s, 1H), 7.78-7.76 (m, 1H), 7.53-7.51 (m; 1H), 7.46 (d, J=15.6Hz, 1H), 7.30-7.26 (m, 1H), 7.17-7.14 (m, 1H); 6.36 (d, J=15.6Hz, 1H), 3.28-3.23 (m, 2H), 2.54-2.47 (m, 6H); 2.34 (s, 3H), 2.12 (s, 3H), 0.97 (t, J=7.08,6H) ppm;
13(DMSO-d6,100MHz) 165.5,160.8,158.3,137.3,134.3,129.3,128.6,125.7,125.4,123.3,119.1,116.0,115.8,113.3,52.2,47.0,37.3,13.1,12.4,11.0ppm for C NMR.
Instance 6.N-[2-(diethylin) ethyl]-5-[(E)-and 2-(4-fluoro-2-bromo-carbaniloyl,phenylcarbamoyl)-vinyl]-2, the preparation of 4-dimethyl--1H-pyrrole-3-carboxamide (III-B)
Method according to embodiment 5; With [(4-fluoro-2-bromo-carbaniloyl,phenylcarbamoyl)-methyl]-diethyl phosphonate (IV-B) (24.0g; 65.2mmol) be raw material, get oily matter 31.1g (the HPLC purity 94.1% of compound III-B), this oily matter can directly be used for going on foot down synthetic.The acetonitrile recrystallization must be marked compound (III-B) 25.4g, yield 81.3%.Faint yellow tabular crystal, fusing point: 119-123 ℃; C
22H
28BrFN
4O
2, ESI-MS m/z: [M+H]
+480.51.
1H?NMR(DMSO-d6，400MHz)□＝8.09-8.07(m，1H)，7.58-7.54(m，2H)，7.15(t，J＝8.7Hz，1H)，6.25(d，J＝15.5Hz，1H)，4.90(br，2H)，3.46(t，J＝7.1Hz，2H)，2.69(t，J＝7.1Hz，2H)，2.64(q，J＝7.2Hz，4H)，2.39(s，3H)，2.28(s，3H)，1.09(t，J＝7.2Hz，6H)；
13C?NMR(100MHz，d
6-DMSO)□＝167.7，166.6，156.4(d，J
C-F＝241.2Hz)，136.3(d，J
C-F＝3.1Hz)，135.0，129.5，124.3，124.0，117.8，120.4(d，J
C-F＝6.6Hz)，116.0，(d，J
C-F＝23.3Hz)，111.8，108.0(d，J
C-F＝21.7Hz)，51.4，46.7，36.5，11.4，10.3，9.3。
Instance 7.N-[2-(diethylin) ethyl]-5-[(E)-and 2-(4-fluoro-2-chloro-carbaniloyl,phenylcarbamoyl)-vinyl]-2, the preparation of 4-dimethyl--1H-pyrrole-3-carboxamide (III-C)
According to the method for embodiment 5, (21.1g 65.2mmol) is raw material, preparation target compound (III-C) with [(4-fluoro-2-bromo-carbaniloyl,phenylcarbamoyl)-methyl]-diethyl phosphonate (IV-C).Faint yellow solid, fusing point: 116-122 ℃; C
22H
28ClFN
4O
2, ESI-MS m/z: [M+H]
+435.81.
1H?NMR(400MHz，d
6-DMSO)□＝7.91-7.88(m，1H)，7.56(d，J＝15.5Hz，1H)，7.48-7.44(m，1H)，7.15(t，J＝8.9Hz，1H)，6.18(d，J＝15.5Hz，1H)，4.91(br，2H)，3.44(t，J＝7.0Hz，2H)，2.67(t，J＝7.0Hz，2H)，2.62(q，J＝7.2Hz，4H)，2.39(s，3H)，2.26(s，3H)，1.07(t，J＝7.2Hz，6H)；
13C?NMR(100MHz，d
6-DMSO)□＝167.6，166.6，155.3(d，J
C-F＝242.8Hz)，136.0(d，J
C-F＝3.1Hz)，135.1，129.5，124.3，124.0，121.5，120.2(d，J
C-F＝18.3Hz)，119.6(d，J
C-F＝6.4Hz)，117.8，116.2(d，J
C-F＝22Hz)，111.7，51.4，46.7，36.5，11.5，10.3，6.4。
Instance 8.N-[2-(diethylin) ethyl]-5-[(Z)-and 5-fluoro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl--1H-pyrrole-3-carboxamide (Sutent, I)
Reflux condensing tube is being housed, TM, in the 250mL there-necked flask of nitrogen ingress pipe, (26.9mg, 0.12mmol), (62.9mg 0.24mmol), after vacuum is switched nitrogen, adds anhydrous acetonitrile (150mL), stirring at room 1 hour to triphenylphosphine to add palladium.Under the nitrogen protection; Add N-[2-(diethylin) ethyl]-5-[(E)-2-(4-fluoro-2-iodo-carbaniloyl,phenylcarbamoyl)-vinyl]-2 successively; 4-dimethyl--1H-pyrrole-3-carboxamide (III-A) (13.2g, 25mmol), triethylamine (3.8g, 37.6mmol); About reflux 3 hours, TLC shows that raw material disappears.Concentrating under reduced pressure reclaims solvent acetonitrile, and resistates filters with methylene dichloride (500mL) dissolving, reclaims palladium catalyst.Filtrating is used saturated brine successively, and (2 * 200mL), (5%, 100mL), deionized water is (after 2 * 200mL) washings, dry, concentrated for potassium hydroxide aqueous solution.The gained solid is used ethyl alcohol recrystallization, gets orange/yellow solid 7.8g, yield 78.3%.Fusing point: 215-217 ℃ (literature value 215-217 ℃); C
22H
27FN
4O
2, ESI-MS m/z: [M+H]
+399.30.
1H?NMR(400MHz，CDCl
3)：□13.33(s，1H)，8.90(s，1H)，7.24(s，1H)，7.14(dd，1H，J
1＝8.8Hz，J
2＝2.2Hz)，6.88(td，1H，J
1＝8.8Hz，J
2＝2.2Hz，)，6.78(dd，1H，J
1＝8.1Hz，J
2＝4.3Hz)，6.72(t，1H，J＝4.4Hz)，3.54(q，2H，J＝5.2Hz)，2.71(t，2H，J＝5.9Hz)，2.64(q，4H，J＝6.6Hz)，2.55(s，3H)，2.31(s，3H)，1.05(t，6H，J＝7.2Hz)。HPLC purity 99.6%.
Instance 9.N-[2-(diethylin) ethyl]-5-[(Z)-and 5-fluoro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl--1H-pyrrole-3-carboxamide (Sutent, I)
Reflux condensing tube is being housed, TM, in the 500mL there-necked flask of nitrogen ingress pipe, (59.2mg, 0.26mmol), (138.4mg 0.52mmol), after vacuum is switched nitrogen, adds anhydrous acetonitrile (290mL), stirring at room 1 hour to triphenylphosphine to add palladium.Under the nitrogen protection, add successively embodiment 6 gained oily matter (31.1g, compound III-B HPLC purity 94.1%), triethylamine (8.4g, 83.2mmol), reflux is about 7 hours, TLC shows that raw material disappears.Concentrating under reduced pressure reclaims solvent acetonitrile, and resistates filters with methylene dichloride (800mL) dissolving, reclaims palladium catalyst.Filtrating is used saturated brine successively, and (2 * 200mL), (5%, 100mL), deionized water is (after 2 * 200mL) washings, dry, concentrated for potassium hydroxide aqueous solution.The gained solid is used ethyl alcohol recrystallization, gets orange/yellow solid 17.8g, and with N-(2-diethylin ethyl)-2,4-dimethyl--5-formyl radical-1H-pyrrole-3-carboxamide (V) calculates, yield 74.3%.Gained sample analysis result is identical with instance 8.
Instance 10.N-[2-(diethylin) ethyl]-5-[(Z)-and 5-fluoro-1,2-dihydro-2-oxo--3H-indol-3-yl methylene radical]-2,4-dimethyl--1H-pyrrole-3-carboxamide (Sutent, I)
Reflux condensing tube is being housed, TM, in the 250mL there-necked flask of nitrogen ingress pipe, (84.1mg 0.12mmol), after vacuum is switched nitrogen, adds anhydrous dimethyl formamide (90mL) to add commercial two (triphenylphosphine) palladium chloride (II).Under the nitrogen protection; Add N-[2-(diethylin) ethyl]-5-[(E)-2-(4-fluoro-2-chloro-carbaniloyl,phenylcarbamoyl)-vinyl]-2 successively; 4-dimethyl--1H-pyrrole-3-carboxamide (III-C) (10.9g, 25mmol), salt of wormwood (5.6g, 40.5mmol); Reacted about 12 hours down in 90-100 ℃, TLC shows that raw material disappears.Concentrating under reduced pressure reclaims solvent, and resistates dissolves with methylene dichloride (500mL), filters, and filtrating is used saturated brine successively, and (2 * 200mL), (5%, 100mL), deionized water is (after 2 * 200mL) washings, dry, concentrated for potassium hydroxide aqueous solution.The gained solid is used ethyl alcohol recrystallization, gets orange/yellow solid 7.1g, yield 70.7%.Gained sample analysis result is identical with instance 8.
Claims (14)
1. a formula (III) compound:
Wherein, X is Cl, Br or I.
2. prepare the method for formula as claimed in claim 1 (III) compound, comprising:
Under alkaline condition, make [(4-fluoro-2-halo-carbaniloyl,phenylcarbamoyl)-methyl]-phosphonic acid diester (IV) and N-(2-diethylin ethyl)-2,4-dimethyl--5-formyl radical-1H-pyrrole-3-carboxamide (V) carries out condensation reaction,
Wherein, X is Cl, Br or I, and R is methyl or ethyl.
3. according to the method for claim 2; It is characterized in that this is reflected in the polar aprotic solvent carries out, and described polar aprotic solvent is selected from THF, 1,4-dioxane, acetonitrile, N; At least a in dinethylformamide and the DMAC N,N.
4. according to the method for claim 3, wherein said polar aprotic solvent is acetonitrile or N, dinethylformamide.
5. according to the method for claim 2, it is characterized in that said alkali is selected from 1, at least a in 8-diazabicyclo [5.4.0] 11 carbon-7-alkene, triethylamine, sodium hydroxide, Lithium Hydroxide MonoHydrate, Pottasium Hydroxide, cesium carbonate and the salt of wormwood.
6. according to the method for claim 5, wherein alkali is Lithium Hydroxide MonoHydrate or Pottasium Hydroxide.
7. method for preparing Sutent (I) comprises:
Make formula (III) structural compounds in polar aprotic solvent, utilize under the condition of palladium compounds as metal catalyst and weak base existence, carry out the molecule inner ring condensation reaction
Wherein, X is Cl, Br or I.
8. according to the method for claim 7, it is characterized in that in polar aprotic solvent, carrying out, said polar aprotic solvent is selected from THF, 1,4-dioxane, acetonitrile, N, at least a in dinethylformamide and the DMAC N,N.
9. according to Claim 8 method, wherein said solvent is acetonitrile or N, dinethylformamide.
10. according to the method for claim 7, it is characterized in that said metal catalyst is Palladous chloride, palladium, two (triphenylphosphine) palladium chloride or palladium-triphenylphosphine complex.
11., it is characterized in that said alkali is selected from least a in diisopropylethylamine, triethylamine, cesium carbonate and the salt of wormwood according to the method for claim 7.
12. according to the method for claim 11, wherein said alkali is triethylamine.
13. a method for preparing Sutent comprises:
(1) in polar aprotic solvent, under the alkaline condition, make [(4-fluoro-2-halo-carbaniloyl,phenylcarbamoyl)-methyl]-phosphonic acid diester (IV) and N-(2-diethylin ethyl)-2,4-dimethyl--5-formyl radical-1H-pyrrole-3-carboxamide (V) carries out condensation reaction,
(2) reaction solution that step (1) is obtained filters, and concentrates, and gets enriched material; Perhaps the reaction solution that obtains in the step (1) is carried out separation and purification, thereby obtain pure formula (III) compound;
(3) under the condition of palladium compounds, make the enriched material or pure formula (III) structural compounds that obtain in the step (2) carry out ring-closure reaction as metal catalyst and weak base existence,
In above chemical formula, X is Cl, Br or I, and R is methyl or ethyl.
14. the application of formula (III) compound in the preparation Sutent according to claim 1.
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| CN101333215A (en) * | 2008-07-29 | 2008-12-31 | 南京工业大学 | Method for synthesizing sunitinib alkali |
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| 刘彪，等.舒尼替尼的合成.《中国医药工业杂志》.2007,第38卷(第8期),539－541. * |
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