CN102858739A - A process for amidation of pyrrole carboxylate compounds - Google Patents
A process for amidation of pyrrole carboxylate compounds Download PDFInfo
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- CN102858739A CN102858739A CN2010800662651A CN201080066265A CN102858739A CN 102858739 A CN102858739 A CN 102858739A CN 2010800662651 A CN2010800662651 A CN 2010800662651A CN 201080066265 A CN201080066265 A CN 201080066265A CN 102858739 A CN102858739 A CN 102858739A
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- 0 CC1(C(C2)C1C1)C3(C)C(C)(C4)*2C4(*)C2[C@@]1C32 Chemical compound CC1(C(C2)C1C1)C3(C)C(C)(C4)*2C4(*)C2[C@@]1C32 0.000 description 2
- BRZYBFNUINXZMJ-UHFFFAOYSA-N CCN(CC)CCNC(c1c(C)[nH]c(C=O)c1C)=O Chemical compound CCN(CC)CCNC(c1c(C)[nH]c(C=O)c1C)=O BRZYBFNUINXZMJ-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
Abstract
The present invention relates to a process of amidation of pyrrole carboxylate compounds, including indolone-substituted pyrrole carboxylate compounds, characterized by using a cyclic alkyltriphosphonate anhydride coupling agent of formula (4) wherein A is C1-C6 alkyl group, preferably n-propyl group and to the use of the cyclic alkyltriphosphonate anhydride coupling agent of formula (4) in making pyrrole carboxamides.
Description
Some pyrroyl aminated compounds is important medical compounds.For example Sutent (chemically be (Z)-N-[2-(diethylamino) ethyl of formula (I)]-5-(5-fluoro-2-oxo-2,3-dihydro-1H-indoles-3-ylidenylmethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide)
Be developed for the preparation of the medicine that is used for the treatment of patients with gastrointestinal stromal tumors (GIST) and metastatic renal cell cancer.On it and the many structures similarly the pyrroyl aminated compounds be disclosed simultaneously among the WO 01/60814 (EP 1255752, and US 6573293).Other has on the structure of similar medicine activity similarly the pyrroyl aminated compounds and for example has been disclosed among WO2004/76410, WO 2006/127961, WO 2007/81560, the WO 2008/33562.
The Sutent molecule has an asymmetric pair of key between indole ring and pyrrole ring.This compound is with (Z) configuration form list marketing on the described pair of key.
This compound can form acid salt, Sutent L MALIC ACID salt for example, and it is the activeconstituents in the medicament production (for example being sold with trade(brand)name SUTENT by Pfizer).
Committed step on preparation Sutent and the structure in the currently known methods of relevant pyrroyl amine compound is included in corresponding amine in suitable stage of reaction sequence and the amidate action of suitable pyrroles's carboxylic acid, wherein can the optional activation carboxyl for amidate action.
Can in WO 01/60814, find the example of the method for this generation Sutent.With 5-formyl radical-2,4-dimethyl-1H-pyrroles-3-formic acid (III)
With N, N-diethylamino ethamine (II)
In dimethyl formamide, exist lower in alkali (triethylamine), react under the effect of the coupling agent of molar excess a little, described coupling agent is the mixture of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide [EDCI] and I-hydroxybenzotriazole [HBT].Then with the product (IV) that obtains
With 5-fluoro-1,3-Indolin-2-one (V)
In inert solvent, reaction in the presence of alkali is to generate the Sutent of expectation.
The people such as Sun disclose alternative reaction scheme at J.Med.Chem. among 2003,46, the 1116-1119.In this article, with described 5-formyl radical-2,4-dimethyl-1H-pyrroles-3-formic acid (III) at first with 5-fluoro-1,3-Indolin-2-one (V) reacts in ethanol and in the presence of piperidines alkali, to generate acid (VI)
Then by amine (II) under the effect of EDCI and HBT coupling agent with acid (VI) amidation.
As apparent from the alternative embodiment 80 of WO 01/60814, the yield of described amidate action very low (43%).
Disclose through improved amidation method among the WO 03/070725 and among the WO 05/023765, wherein for amidate action, by the heterocyclic group of covalent bonding, for example by the carbonyl on 1H-imidazoles-1-base activation pyrrole ring.With activated intermediate, compound (IIIa) for example
May in a step, react with amine (II) and indolone (V), to generate the Sutent (embodiment 1 of WO ' 725) of expectation.
The activation of pyrrolylcarbonyl needs extra reactions steps (for example, compound (IIIa) is by corresponding acid (III) and carbonyl dimidazoles preparation), comprises the separation activated intermediate that produces and the remnants that remove disadvantageous reagent.In addition, the formyl radical of compound (IV) can react with activating reagent and/or with amine (II) in side reaction, and this also is undesirable.
Desirable is to have a kind of alternative for preparing the relevant oxindole compounds that replaces through the pyrroles on Sutent and other structure, and described compound has amide substituents in pyrrole ring, and wherein said method does not show above-mentioned shortcoming.
The invention summary
The present invention relates to the method for a kind of amidation minaline ester cpds (comprise indolone replace minaline ester cpds), it is characterized in that adopting cheapness, nontoxic and effectively be used for the specific coupling agent of amidate action.
In first aspect, the invention provides a kind of method for preparing general formula (1) compound
Wherein,
R is the group of hydrocarbon chain that comprises 1 to 20 carbon of straight chain, side chain or ring-type, carbon on the wherein said chain optional position can be randomly by one to four nitrogen, oxygen or sulphur atom displacement, and wherein chain hydrogen can be randomly by one to four amino, hydroxyl, oxo base, thio group, thiocarbonyl group (thiono-), halogeno-group replacement arbitrarily
Z be hydrogen or
Group,
W is hydrogen or OR
3Group,
C=X is C=O group, C=N-R
4Group,
Group or
Group,
Y is hydrogen or at least a halo group, C1-C10 alkyl, carboxyl, amino and/or sulfuryl amine group,
R
1, R
2, R
3, R
4, R
5, R
6In each be independently selected from hydrogen or randomly contain one or more other N, O or the C1-C10 alkyl of S atom,
Described method comprises the steps: formula (2) compound
Amine with formula (3)
NH
2-R (3)
Reaction in the presence of the cyclic alkyl triphosphine acid anhydrides coupling agent of formula (4)
Wherein A is the C1-C6 alkyl, is preferably n-propyl.
Aspect specific, the Z group represents
Group, wherein W hydrogen preferably, and C=X preferably the C=O group or
Group, and R
1, R
2It is methyl.Therefore, preferred formula (2) compound is formula (2a) or formula (2b) compound
Again one specific aspect, radicals R is N, N-diethylamino ethyl, and the amine of formula (3) is the N of formula (3a), N-diethylamino ethamine
Correspondingly, preferred formula (1) compound is formula (1a) or (1b) compound
Obviously, compound (1b) is equivalent to Sutent.
Again one specific aspect, the reaction of formula (2) compound and formula (3) amine is in the presence of the coupling agent of formula (4), in inert solvent or in the amine (3) as solvent, typically in envrionment temperature or near carrying out under the envrionment temperature.Randomly, reaction product is separated also purifying from reaction mixture.
If the part of the X in the Z group of formula as hereinbefore defined (1) or (2) compound is not equivalent to inferior indoles ketone group
Wherein, Y is hydrogen or at least a halo group, C1-C10 alkyl, carboxyl, amino and/or sulfuryl amine group, and the fluoro group (is hydrogen at W for example typically, and C=X is in the situation of C=O group), aforesaid method can comprise that the C=X Partial Conversion with the Z group is the next step of described inferior indoles ketone group so.In the example of this conversion, formula (1a) compound can be converted into Sutent (1b).
In second aspect, the invention provides the first method of the Sutent of preparation formula (1b), it may further comprise the steps order:
-in the presence of the ring-type propyl group triphosphine acid anhydrides of formula (4a) with the N of formula (3), N-diethylamino ethamine is the amidation of formula (2a) compound, and
-the acid amides (1a) that will so obtain and the 5-fluoro-1 of formula (5), the reaction of 3-Indolin-2-one
In addition, the invention provides the second method of the Sutent of preparation formula (1b), it may further comprise the steps order:
-with formula (2a) compound and 5-fluoro-1,3-Indolin-2-one (5) reaction is with production (2b) compound
-in the presence of the ring-type propyl group triphosphine acid anhydrides of formula (4a), use the N of formula (3a), N-diethylamino ethamine is with the amidation of formula (2b) compound.
In the third aspect, the invention provides formula (4) compound, particularly formula (4a) compound for the preparation of general formula (1) compound, typically preparation formula (1a) and/or (1b) the new purposes in the method for compound
In fourth aspect, the present invention relates to the purposes of cyclic alkyl triphosphine acid anhydrides coupling agent in preparation pyrroyl aminated compounds of formula (4).
Detailed Description Of The Invention
The present invention relates to the improved amidation method for the preparation of the pyrroyl amine compound of general formula (1)
Wherein,
R is the group of hydrocarbon chain that comprises 1 to 20 carbon of straight chain, side chain or ring-type, carbon on the wherein said chain optional position can be randomly by one to four nitrogen, oxygen or sulphur atom displacement, and wherein chain hydrogen can be randomly by one to four amino, hydroxyl, oxo base, thio group, thiocarbonyl group, halogeno-group replacement arbitrarily
Z be hydrogen or
Group,
W is hydrogen or OR
3Group,
C=X is C=O group, C=N-R
4Group,
Group or
Group,
Y is hydrogen or at least a halo group, C1-C10 alkyl, carboxyl, amino and/or sulfuryl amine group,
R
1, R
2, R
3, R
4, R
5, R
6In each be independently selected from hydrogen or randomly contain one or more other N, O or the C1-C10 alkyl of S atom.
Aspect specific, the Z group represents
Group, wherein W hydrogen preferably, and C=X preferably the C=O group or
Group, and R
1, R
2It is methyl.
Preferred formula (1) compound is formula (1a) or compound (1b)
Obviously, compound (1b) is equivalent to Sutent.
General formula (1) compound useful as drug active compound, for example Sutent and analogue thereof perhaps can be used as their intermediate of preparation.Its industrial usability can obtain from the instruction of WO01/60814, WO 03/070725, WO 05/023765, U. S. application 2006/0009510 etc.
In general, formula (1) compound is known, and can prepare them by various programs.Crucial synthetic route comprises a reactions steps, and this reactions steps comprises with the amine of formula (3) carries out amidate action to the carboxylic acid of formula (2).In typical example, the amine of formula (3) is the N of formula (3a), N-diethylamino ethamine
Because known amidation program has number of drawbacks in the method for preparation formula (1) compound, especially low yield the objective of the invention is the improvement of this aspect.
With amine the carboxylic acyloxy amination is needed coupling agent usually, this coupling agent is the reagent in conjunction with water, and described water produces by following amidate action:
-COOH+NH
2-R→-CONH-R+H-OH。
In conjunction with water molecular balance is changed to the direction that forms acid amides.
The currently known methods of the Sutent that usually has formula (1) from the acid of general formula (2) preparation and analogue and/or intermediate, usually with the carbodiimide coupling agent, be used for being connected to the amidate action on the carboxyl of pyrrole ring such as EDCI.Carbodiimide compound is poisonous compound, and it only provides the amidation of medium yield, and is difficult to remove from reaction mixture after finishing amidate action.As mentioned, in preparing the method for Sutent, the yield of the amidate action of carbodiimide-mediated only is 43%.Multiple other coupling agent can be used for amidate action in theory, but neither one is after deliberation for the preparation of Sutent and analogue thereof in them, except the benzotriazole of mentioning among the embodiment 129 of WO 01/60814 and the WO 2007/034272-1-base oxygen base three (dimethylaminos)-
Hexafluorophosphate (BOP) in addition.This coupling agent provides good amidation yield, but the by product of BOP itself and generation thereof is highly toxic compound, needs extra processing cost and security measures, especially on technical scale.
The invention provides the coupling agent by employing formula (4), the amidate action between general formula (2) and (3) compound, wherein A is the C1-C6 alkyl, is preferably n-propyl.This compound is cyclic phosphonic acid anhydrides, and the water reaction that discharges during itself and the amidate action forms linear triguaiacyl phosphate:
The ring-type of above scheme and linear triguaiacyl phosphate all in the soluble in water and multiple organic solvent, therefore can easily be removed from reaction product.They are nontoxic compounds, can process by standard approach.Amidate action carries out usually at ambient temperature, has almost quantitative conversion.
Formula (4) compound for example is disclosed among the WO 2005/014604.
The three n-propyl ring-type triphosphine acid anhydrides that preferred general formula (4) compound is formula (4a) (2,4,6-, 3 third-1-base-1,3,5-trioxa-2,4,6-triphosphine-2,4,6-trioxide),
It can obtain by commercial sources, and is referred to as T3P in this article.In favourable mode, it at suitable solvent, for example in the solution in ethyl acetate or the DMF, is used for method of the present invention.
Now explain without limitation the present invention with two kinds of methods that prepare Sutent (1b), these two kinds of methods are summarized in the following scheme.Described method comprises that the coupling agent of use formula (4a) is as the preferred member of general formula (4) compound.
The starting raw material 5-formyl radical-2 of formula (2a), 4-dimethyl-1H-pyrroles-3-formic acid has been disclosed among the WO 01/060814.
First method of the present invention may further comprise the steps order:
-in the presence of the ring-type propyl group triphosphine acid anhydrides of formula (4a), with the N of formula (3a), N-diethylamino ethamine is the amidation of formula (2a) compound, and
-formula (1a) compound that will so obtain and the 5-fluoro-1 of formula (5), the reaction of 3-Indolin-2-one
In the first step, compound (2a) and amine (3a) are reacted in inert solvent in the presence of T3P coupling agent (4a).Because amine (3a) is liquid, also can be used as the solvent of this reaction.This amidate action can carry out in room temperature or under near room temperature (for example 10-40 ℃ scope, preferred approximately 25 ℃), and usually finishes in several hours.Reaction process can for example be monitored by TLC or HPLC by conventional analytical technology, and this reaction can stop after the degree of conversion that obtains expectation.The aftertreatment of reaction mixture represents described mixture basically in the distribution of (for example water and hydrocarbon or between the hydrocarbon of chlorination) between water and the organic phase, and from organic phase separated product.If necessary, can randomly after the resistates of the resistates that extracts employed amine or T3P reagent, further crude product be passed through recrystallization or redeposition purifying.The product (1a) of expectation can be used as solid obtaining above 90% yield.
Compound (1a) can be separated from reaction mixture or separates with purification solvent as free alkali or with the form of acid salt (for example hydrochloride).
Alternately, the reaction mixture of inclusion compound (1a) or through the reaction mixture (for example compound (1a) is at amine (3a) or the solution in organic solvent) of aftertreatment can in the situation that not separating compound (1a) be used for next reactions steps.Then two steps of first method all can be carried out in " one pot " device.
In second step, by conventional procedure, for example by disclosed method E among the WO 01/060814 formula (1a) compound is converted into Sutent (1b).Usually, with compound (1a) and the 5-fluoro-1 of equimolar amount, 3-Indolin-2-one (5) in inert solvent, for example in the fatty alcohol, preferably reacts in the presence of alkali at elevated temperatures.Can product be separated from reaction mixture by the program of routine, and carry out purifying if necessary.
Second method of the present invention consists essentially of the counter-rotating order of described amidation and condensation step, especially following steps order:
-with formula (2a) compound and 5-fluoro-1,3-Indolin-2-one (5) reacts with production (2b) compound
-in the presence of the ring-type propyl group triphosphine acid anhydrides of formula (4a), with the N of formula (3a), N-diethylamino ethamine is with the amidation of formula (2b) compound.
In the first step, formula (2a) compound and 5-fluoro-1,3-Indolin-2-one (5) in inert solvent, for example in fatty alcohol, react in the presence of organic or inorganic alkali at elevated temperatures.By conventional procedure, for example by precipitation, product is separated from reaction mixture, and carry out purifying if necessary.Can for example monitor reaction process by TLC or HPLC by conventional analytical technology, and this reaction can stop after the degree of conversion that obtains expectation.The details of this synthesis program can find in WO 2004/76410, WO 2006/127961 or in WO 2007/81560.
Typically, formula (2b) compound especially separates with the crystalline state that is conducive to store with further processing with solid form.Can be randomly with its with the salt of alkali, for example separate with sodium, potassium, magnesium, calcium or lithium salts.
In second step, compound (2b) and amine (3a) in the presence of T3P coupling agent (4a), are reacted in inert solvent.Described inert solvent is organic solvent, polar organic solvent typically, and most preferably be dipolar aprotic solvent, for example DMF, acetonitrile or methyl-sulphoxide.Temperature of reaction is essentially room temperature or near room temperature (10-40 ℃).Can by conventional analytical technology, for example monitor reaction process by TLC or HPLC.After the conversion that reaches expectation, product is separated from reaction mixture.Typically, can after water is with its dilution, it be precipitated from reaction mixture.Coupling agent rests in the aqueous mother liquor fully.With separated product washing and dry.If necessary, can for example pass through recrystallization (for example from ethanol) with its purifying.
The Sutent (1b) of expectation can be used as solid obtaining above 90% yield.
As in the method before, described two steps can all be carried out in the one kettle way device.
Randomly can be with compound (1b) from the reaction mixture of any aforesaid method, to separate (or being converted into subsequently described salt) with various forms inorganic or the organic acid acid salt; These sour examples are hydrochloric acid, Hydrogen bromide, sulfuric acid, methylsulfonic acid, Phenylsulfonic acid, tosic acid, formic acid, acetic acid, toxilic acid, fumaric acid, oxalic acid, citric acid, oxysuccinic acid or succsinic acid without limitation.
Formula (1b) compound and/or its acid salt be its separated form usefully preferably, is more preferably solid-state form, such as any crystal or amorphous form; Described solid-state form is also contained solvate and hydrate.Because the industrial application of expection preferably has and is higher than 95% chemical purity, especially has the compound (1b) and the salt thereof that are higher than 99% chemical purity.
Especially the suitable acid salt of compound (1b) is Sutent-L MALIC ACID salt.
Other general formula (1) compound can prepare in substantially similar mode.For example, method of the present invention can be for the preparation of formula (1c) compound and the pharmacy acceptable salt thereof that are disclosed among WO 2004/76410 and the WO 2007/34272
Further illustrate the present invention by following examples.These embodiment are nonrestrictive and do not limit the scope of the invention.
Embodiment
Embodiment 1-(2a) is to the conversion of (1a)
Under stirring at room, to acid derivative
(2a)(835mg, ~ 5mmol) drip propane phosphoric anhydride (T3P) (10ml, 50%EtOAc solution) in the solution in N-diethyl ethylenediamine (10ml), and in 1.5 hours, finish.With the further stirred overnight of reaction mixture that produces.Add water (25ml) and methylene dichloride (25ml), and mixture was stirred 25 minutes.Dichloromethane layer is separated also concentrated so that oily mater to be provided in a vacuum.With this oily matter and ethyl acetate (50ml) and sodium carbonate solution (4%, 25ml) mix, and stirred 30 minutes at 70 ℃.After cooling, ethyl acetate layer is separated and water (10ml) washing dry (Na
2SO
4) and concentrated so that yellow solid to be provided
(1a)(1.35g).
Embodiment 2-(2a) is to the conversion of (1a)
Under stirring at room, to acid derivative
(2a)(835mg, ~ 5mmol) at N, drip (utilizing adding set) propane phosphoric anhydride (T3P) (6ml, 50%EtOAc solution) in the solution in the N-diethylamino ethamine (10ml), and in 1.5 hours, finish.Add water (25ml) and methylene dichloride (50ml), and the mixture that produces was stirred 20 minutes.Dichloromethane layer is separated, water (20ml) washing, and concentrated so that oily mater to be provided in a vacuum.This oily matter and ethyl acetate (50ml) and HCl solution (1M, 12ml) are mixed, and stirring at room 30 minutes.Then, mixture is alkalized to pH ~ 10.Ethyl acetate layer is separated, water (10ml) washing, and concentrated so that yellow solid to be provided in a vacuum
(1a)(1.3g).
Embodiment 3-(1a) is to the conversion of (1b)
To the 5-fluoro-1 of 150mg formula (5), interpolation ~ 0.5ml tetramethyleneimine (10) in 3-Indolin-2-one and the mixture of 450mg aldehyde derivatives (1a) in 10ml ethanol.With mixture heating up to refluxing 3 hours.After being cooled to room temperature, leach formed solid Sutent (1b).Concentrated filtrate also is dissolved in resistates in the 2ml ethanol.With clear solution at room temperature overnight storage to generate 2 batches of solid Sutents.
In vacuum, after the dried overnight, amount to the solid Sutent that obtains the 310mg expectation, (yield: 77%) at 40 ℃.
Embodiment 4-(2a) is to the conversion of (2b)
Interpolation ~ 0.5ml the piperidines (10) in the mixture in 6ml ethanol to 200mg 5-fluorine oxindole (5) and 266mg aldehyde (2a), and mixture heating up to 60 ℃ spent the night.After being cooled to room temperature, leaching solid and use twice of 5ml1M HCL solution washing.With solid in 40 ℃ of dried overnight under vacuum.Obtain the product (2b) of 390mg expectation.
Embodiment 5-(2b) is to the conversion of Sutent (1b)
Add 1.5ml N in the 150mg in 3ml DMF (2b), N-diethylamino ethamine is to form solution.Then utilize syringe pump in 50% solution of propane phosphonic acid cyclic acid anhydride in DMF that in 1.5 hours, adds 0.6ml under the envrionment temperature.At room temperature continue to stir to spend the night.Then the propane phosphonic acid acid anhydride that adds 0.1ml in DMF 50% solution and continue to stir 2 hours in room temperature.Add 50ml water and filter formed suspension.Solid is washed with water twice.At 40 ℃, under vacuum, after dry 3 hours, obtain about 150mg solid Sutent.Obtain analytic sample by recrystallization in ethanol.
Through describing the present invention, it is evident that to those skilled in the art, in this article in the actual enforcement of described concept and embodiment, can easily make maybe and can change and change to further by practice knowledge of the present invention, and not break away from by the spirit and scope of the present invention defined by the following claims.
Claims (17)
1. the method for preparing general formula (1) compound
Wherein,
R is the group of hydrocarbon chain that comprises 1 to 20 carbon of straight chain, side chain or ring-type, carbon on the optional position of wherein said chain can be randomly by one to four nitrogen, oxygen or sulphur atom displacement, and wherein chain hydrogen can be randomly by one to four amino, hydroxyl, oxo base, thio group, thiocarbonyl group, halogeno-group replacement arbitrarily
Z be hydrogen or
Group,
W is hydrogen or OR
3Group,
C=X is C=O group, C=N-R
4Group,
Group or
Group,
Y is hydrogen or at least a halo group, C1-C10 alkyl, carboxyl, amino and/or sulfuryl amine group,
R
1, R
2, R
3, R
4, R
5, R
6In each be independently selected from hydrogen or randomly contain one or more other N, O or the C1-C10 alkyl of S atom,
Described method comprises the steps: formula (2) compound
Amine with formula (3)
NH
2-R (3)
Reaction in the presence of the cyclic alkyl triphosphine acid anhydrides coupling agent of formula (4)
Wherein A is the C1-C6 alkyl.
2. according to claim 1 method, the A in its Chinese style (4) is n-propyl.
3. according to claim 1 and 2 method, wherein,
Group Z represents
Group, wherein W hydrogen preferably, and C=X preferably the C=O group or
Group,
And R
1, R
2It is methyl.
4. method according to claim 1-3, wherein said formula (2) compound are formula (2a) or formula (2b) compound
5. method according to claim 1-4, wherein radicals R is N, N-diethylamino ethyl, and the amine of formula (3) is the N of formula (3a), N-diethylamino ethamine
6. method according to claim 1-5, its Chinese style (1) compound are formula (1a) or (1b) compound
7. method according to claim 1-6, the reaction of the amine of its Chinese style (2) compound and formula (3) is carried out in inert solvent or in the amine (3) as solvent in the presence of the coupling agent of formula (4).
8. according to claim 7 method, wherein said reaction is in envrionment temperature or near carrying out under the envrionment temperature.
9. method according to claim 1-8 is wherein separated the reaction product of formula (1) from reaction mixture, and purifying randomly.
10. method according to claim 1-9, the Z group of its Chinese style (1) or (2) compound is not equivalent to inferior indoles ketone group
Wherein, Y is hydrogen or at least a halo group, C1-C10 alkyl, carboxyl, amino and/or sulfuryl amine group,
Described method comprises that further the C=X Partial Conversion with the Z group is the step of described inferior indoles ketone group.
11. method according to claim 10, wherein W is hydrogen, and C=X is the C=O group, and R is hydrogen or N, N-diethylamino ethyl, R
1And R
2Be methyl, and Y is fluorin radical.
12. the method for preparation formula (1b) compound
It may further comprise the steps order:
-with formula (2a) compound
With the N of formula (3a), N-diethylamino ethamine
Amidation in the presence of the ring-type n-propyl triphosphine acid anhydrides of formula (4a), and
-the acid amides (1a) that will so obtain
With the 5-fluoro-1 of formula (5), the reaction of 3-Indolin-2-one
13. the method for preparation formula (1b) compound, it may further comprise the steps order:
-with formula (2a) compound and 5-fluoro-1,3-Indolin-2-one (5) reacts with production (2b) compound,
-in the presence of the ring-type propyl group triphosphine acid anhydrides of formula (4a), with the N of formula (3a), N-diethylamino ethamine is with the amidation of formula (2b) compound.
14. according to claim 12 or 13 method, wherein compound (1b) is separated from reaction mixture.
15. method according to claim 14 wherein obtains compound (1b) or be translated into acid salt with acid salt, and preferably, described acid salt is Sutent L MALIC ACID salt.
16. the purposes of formula (4) compound in the method for preparing general formula (1) compound,
Wherein A is the C1-C6 alkyl, is preferably n-propyl.
17. purposes according to claim 16, its formula of (1) compound are formula (1a) and/or (1b) compound.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/EP2010/001609 WO2011110199A1 (en) | 2010-03-10 | 2010-03-10 | A process for amidation of pyrrole carboxylate compounds |
Publications (1)
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| CN102858739A true CN102858739A (en) | 2013-01-02 |
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| CN2010800662651A Pending CN102858739A (en) | 2010-03-10 | 2010-03-10 | A process for amidation of pyrrole carboxylate compounds |
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| Country | Link |
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| EP (1) | EP2545034A1 (en) |
| CN (1) | CN102858739A (en) |
| WO (1) | WO2011110199A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109485639A (en) * | 2018-12-20 | 2019-03-19 | 石药集团中奇制药技术（石家庄）有限公司 | A kind of Sutent preparation method |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104114550A (en) * | 2012-03-23 | 2014-10-22 | 劳拉斯实验室私人有限公司 | An improved process for the preparation of sunitinib and its acid addition salts |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1439005A (en) * | 2000-02-15 | 2003-08-27 | 苏根公司 | Pyrrole substituted 2-indolinone protein kinase inhibitors |
| CN1823079A (en) * | 2003-07-21 | 2006-08-23 | 科莱恩产品（德国）有限公司 | Method for the production of cyclic phosphonic acid anhydrides |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003070725A2 (en) | 2002-02-15 | 2003-08-28 | Pharmacia & Upjohn Company | Process for preparing indolinone derivatives |
| US7452913B2 (en) | 2003-02-24 | 2008-11-18 | Pharmacia & Upjohn Company | Polymorphs of pyrrole substituted 2-indolinone protein kinase inhibitors |
| WO2005023765A1 (en) | 2003-09-11 | 2005-03-17 | Pharmacia & Upjohn Company Llc | Method for catalyzing amidation reactions by the presence of co2 |
| US20060009510A1 (en) | 2004-07-09 | 2006-01-12 | Pharmacia & Upjohn Company Llc | Method of synthesizing indolinone compounds |
| WO2006127961A1 (en) | 2005-05-26 | 2006-11-30 | The Scripps Research Institute | Enhanced indolinone based protein kinase inhibitors |
| KR101050906B1 (en) | 2005-09-19 | 2011-07-20 | 화이자 프로덕츠 인크. | Solid salt form of pyrrole substituted 2-indolinones |
| US20080269212A1 (en) | 2005-12-29 | 2008-10-30 | The Scripps Research Institute | Amino acid derivatives of indolinone based protein kinase inhibitors |
| KR101507375B1 (en) | 2006-09-15 | 2015-04-07 | 엑스커버리 홀딩 컴퍼니 엘엘씨 | Kinase inhibitor compounds |
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- 2010-03-10 WO PCT/EP2010/001609 patent/WO2011110199A1/en active Application Filing
- 2010-03-10 EP EP10710795A patent/EP2545034A1/en not_active Withdrawn
- 2010-03-10 CN CN2010800662651A patent/CN102858739A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1439005A (en) * | 2000-02-15 | 2003-08-27 | 苏根公司 | Pyrrole substituted 2-indolinone protein kinase inhibitors |
| CN1823079A (en) * | 2003-07-21 | 2006-08-23 | 科莱恩产品（德国）有限公司 | Method for the production of cyclic phosphonic acid anhydrides |
Non-Patent Citations (3)
| Title |
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| ARCHIMICA: "Coupling Agent T3P-The Water Scavenger", 《ARCHIMICA》 * |
| LI SUN ET AL.: "Discovery of 5-[5-Fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-Diethylaminoethyl)amide, a Novel Tyrosine Kinase Inhibitor Targeting Vascular Endothelial and Platelet-Derived Growth Factor Receptor Tyrosine", 《J. MED. CHEM.》 * |
| 吴长增等: "一种新型缩合试剂——正丙基膦酸酐", 《化学试剂》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109485639A (en) * | 2018-12-20 | 2019-03-19 | 石药集团中奇制药技术（石家庄）有限公司 | A kind of Sutent preparation method |
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| Publication number | Publication date |
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| EP2545034A1 (en) | 2013-01-16 |
| WO2011110199A1 (en) | 2011-09-15 |
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