CN103242240B - A kind of intermediate, its salt and preparation method thereof of sulfamide compound - Google Patents
A kind of intermediate, its salt and preparation method thereof of sulfamide compound Download PDFInfo
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- CN103242240B CN103242240B CN201210030212.5A CN201210030212A CN103242240B CN 103242240 B CN103242240 B CN 103242240B CN 201210030212 A CN201210030212 A CN 201210030212A CN 103242240 B CN103242240 B CN 103242240B
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- MOZNZNKHRXRLLF-UHFFFAOYSA-N CN(CC1)CCN1c(cc1)ccc1N Chemical compound CN(CC1)CCN1c(cc1)ccc1N MOZNZNKHRXRLLF-UHFFFAOYSA-N 0.000 description 1
- WDHHNLYKYIZTOG-UHFFFAOYSA-N Cc(cn1)c(NC)nc1Cl Chemical compound Cc(cn1)c(NC)nc1Cl WDHHNLYKYIZTOG-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention discloses the compound as shown in formula III.The invention also discloses the preparation method of the salt of the sulfamide compound as shown in formula III, comprising: in solvent, formula IV compound and compound 2 are carried out linked reaction, temperature is 35 DEG C ~ 200 DEG C; n
2=1 ~ 4; Described X is can by the protonic acid of underpressure distillation removing.The invention also discloses the preparation method of the sulfamide compound such as formula I: 1. obtain formula III compound by above-mentioned preparation method; 2., in solvent, 0 DEG C ~ solvent reflux temperature, formula III compound step 1. obtained and alkali react; Described X is protonic acid; Described n
2=1 ~ 4.The invention also discloses such as formula the compound shown in IV.Preparation method's reaction conditions of the present invention is gentle, yield is high, purifying is simple and be applicable to suitability for industrialized production.
Description
Technical field
The present invention relates to a kind of intermediate of sulfamide compound, its salt and preparation method thereof.
Background technology
TG101209, chemical name be (the N-tertiary butyl-3-(5-methyl-2-[4-(4-methyl isophthalic acid-piperazine) anilino]-4-aminopyrimidine)-benzsulfamide, has structural formula:
TG101209 is by TargeGen company of the U.S., with Harvard Medical School, and the selective depressant of the JAK2 protein kinase of the unit consolidation such as the Mayo clinic of bright Buddhist nun's soda exploitation; With extracellular experiment display in preclinical cell, it optionally can suppress V617F sudden change and the MPLW515L sudden change of the JAK2 gene of the major reason causing myeloproliferative disease; There is treatment polycythemia vera (PolycythemiaVera, PV), primary thrombocytosis (EssentialThrombocythemia, ET), the activity of the diseases such as PMF (PrimaryMyelofibrosis, PMF).Its biological activity is reported by people such as A.Pardanani, is published in (A.Pardanni, etal, Leukemia, 2007,21,1658-1668) on magazine Leukemia in 2007.The patent WO2007/053452A1 of TargeGen company of U.S. application reports a kind of preparation method and the structure activity relationship of this compound and analogue thereof; But it is low that the method reported also exists yield, purification difficult, be unfavorable for the problems such as extensive preparation.
Particularly, the method for TargeGen company synthesis TG101209 utilizes compound 4 and 2 to carry out reacting generating compound 5, and then compound 5 and compound 6 carry out coupling and obtain target product TG101209 under the catalysis of palladium metal.The productive rate of two-step reaction is respectively 63% and 59%, and overall yield only has 37%.Particularly its linked reaction needs expensive palladium metal reagent and phosphorus part to carry out catalysis; And adopt microwave heating to be unfavorable for the suitability for industrialized production of this reaction.The equation of the method is described below:
Summary of the invention
Technical problem to be solved by this invention is: in order to overcome the existing TG101209 of preparation (formula I) method in low, the purification difficult of severe reaction conditions, product yield and be unfavorable for the defects such as suitability for industrialized production, and provide a kind of intermediate such as formula the TG101209 sulfamide compound shown in I, its salt and and preparation method thereof.Preparation method's reaction conditions of the present invention is gentle, yield is high, purifying is simple and be applicable to prepare in a large number and suitability for industrialized production.
The invention provides a kind of salt of the sulfamide compound as shown in formula III,
Wherein, described X is the protonic acid that underpressure distillation can be leaned on to remove, and the negative pressure of described underpressure distillation is 15 ~ 30 mmhg, and the temperature of described underpressure distillation is 30 DEG C ~ 60 DEG C; The described protonic acid that underpressure distillation can be leaned on to remove is preferably one or more in hydrogenchloride, trifluoracetic acid, acetic acid, hydrogen bromide, oxalic acid, tartrate and citric acid, is more preferably one or more in hydrogenchloride, trifluoracetic acid and acetic acid; Described n
2=1 ~ 4, being preferably the integer of 1 ~ 4, is 1 or 2 best.
Present invention also offers the preparation method of the salt of the sulfamide compound as shown in formula III, it comprises the following steps: in solvent, and formula IV compound and compound 2 are carried out linked reaction, and temperature of reaction is 35 DEG C ~ 200 DEG C;
Wherein, described n
2=1 ~ 4; Described X is the protonic acid that underpressure distillation can be leaned on to remove, and the negative pressure of described underpressure distillation is 15 ~ 30 mmhg, and the temperature of described underpressure distillation is 30 DEG C ~ 60 DEG C.
Described n
2being preferably the integer of 1 ~ 4, is more preferably 1 or 2.
The described protonic acid that underpressure distillation can be leaned on to remove is preferably one or more in hydrogenchloride, trifluoracetic acid, acetic acid, hydrogen bromide, oxalic acid, tartrate and citric acid, is more preferably one or more in hydrogenchloride, trifluoracetic acid and acetic acid; Wherein, the method for described underpressure distillation can be the method for the underpressure distillation of this area routine.Described hydrogenchloride and hydrogen bromide preferably participate in reaction in form of an aqueous solutions.
The mole dosage of described formula IV compound is more than or equal to the half of the mole dosage of compound 2.Described formula IV compound and the mol ratio of compound 2 are preferably 1.5: 1 ~ 0.5: 1, are more preferably 1: 1.
Reaction system can be reacted in a heated condition.The mode of described heating is preferably oil bath heating, heating in water bath, electric mantle heating or microwave heating etc., is more preferably microwave heating, utilizes microwave heating can Reaction time shorten greatly.When temperature of reaction is 80 DEG C ~ 200 DEG C, reaction system preferably utilizes microwave heating.When temperature of reaction is 35 DEG C ~ 150 DEG C, reaction system preferably utilizes the mode except microwave heating to heat.The operation steps of the mode of described heating and using method all can be selected by the operation steps of this area routine and using method.
When using microwave heating, described temperature of reaction is preferably 80 DEG C ~ 150 DEG C, is more preferably 80 DEG C ~ 120 DEG C.When using the type of heating beyond microwave heating, described temperature of reaction is preferably 80 DEG C ~ 150 DEG C, is more preferably 80 DEG C ~ 90 DEG C.
Described solvent can be the common solvent of this area, is preferably polar solvent, is more preferably alcohols protic solvent or aprotic polar solvent.Described alcohols protic solvent is preferably one or more in Virahol, methyl alcohol, ethanol, n-propyl alcohol, butanols and primary isoamyl alcohol, is more preferably Virahol.Described aprotic polar solvent is preferably one or more in acetonitrile, DMF, N,N-dimethylacetamide and methyl-sulphoxide, is more preferably DMF.The consumption of described solvent is preferably 1mL/g ~ 10mL/g formula IV compound, is more preferably 5mL/g ~ 6mL/g formula IV compound.
The process of described linked reaction is monitored by TLC or LC-MS, as the terminal of reaction when generally disappearing using reaction system compound of formula IV.
After described linked reaction terminates, aftertreatment purifying formula III compound can be carried out.The method of described aftertreatment can be the post-treating method of this area routine, its preferably step comprise: reaction system is cooled to room temperature (25 DEG C ~ 30 DEG C), filters, filter residue organic solvent washing, dry.Better step comprises: the system after reaction being terminated is cooled to room temperature (25 DEG C ~ 30 DEG C), concentrating under reduced pressure except desolventizing, with a small amount of organic solvent (1mL/g ~ 5mL/g crude product) making beating, filter, filter cake solvent wash, drying.Described organic solvent is preferably one or more in ethanol, Virahol, tetrahydrofuran (THF), ethyl acetate and methylene dichloride, is more preferably Virahol.
Described formula IV compound can be obtained by following method: in solvent, compound 1 and protonic acid is reacted, production IV compound;
Wherein, n
2=1 ~ 4; Described protonic acid and X are the protonic acid that underpressure distillation can be leaned on to remove, and the negative pressure of described underpressure distillation is 15 ~ 30 mmhg, and the temperature of described underpressure distillation is 30 DEG C ~ 60 DEG C.
Wherein, described solvent can be the solvent of this area routine, is preferably water and/or polar organic solvent.Described polar organic solvent generally comprises polar aprotic solvent and/or polar aprotic solvent.Described polar aprotic solvent is preferably organic alcohol solvent.Described organic alcohol solvent is preferably methyl alcohol and/or ethanol.Described polar aprotic solvent is preferably one or more in tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, methylene dichloride, chloroform and acetonitrile.The consumption of described solvent is preferably 5mL/g ~ 20mL/g compound 1, is more preferably 8mL/g ~ 15mL/g compound 1.
The described protonic acid that underpressure distillation can be leaned on to remove generally comprise organic proton acid and/or inorganic proton sour.Described organic proton acid is preferably one or more in trifluoracetic acid, acetic acid, oxalic acid, tartrate and citric acid, is more preferably trifluoracetic acid and/or acetic acid.Described inorganic proton acid is preferably hydrogenchloride and/or hydrogen bromide, is more preferably hydrogenchloride.Described hydrogenchloride and hydrogen bromide preferably participate in reaction in form of an aqueous solutions.The concentration of described hydrochloride aqueous solution and the aqueous solution of hydrogen bromide can be the concentration of the hydrochloride aqueous solution of this area routine and the aqueous solution of hydrogen bromide.The volume fraction of described hydrochloride aqueous solution is preferably 36.5%.The volume fraction of described aqueous solution of hydrogen bromide is preferably 47%.
The mole dosage in the reaction of described protonic acid is more than or equal to the mole dosage of compound 1.Described compound 1 and the mol ratio of carrying out the protonic acid reacted with it are preferably 1: 1.0 ~ 1: 2.5, are more preferably 1: 2.
Described n2 is preferably the integer of 1 ~ 4, and better is 1 or 2.
The temperature of described reaction is do not affect normally carrying out of reaction.
The process of described reaction is monitored by TLC or LC-MS, as the terminal of reaction when generally disappearing using compound in reaction system 1.
Aftertreatment purifying formula IV compound also can be carried out after described reaction terminates.Described post-treating method is preferably excessive protonic acid and solvent in distillation removing reaction system.Described distillation is preferably underpressure distillation, and the negative pressure of described underpressure distillation is 15 ~ 30 mmhg, and the temperature of described underpressure distillation is 30 DEG C ~ 60 DEG C, is preferably 35 DEG C ~ 45 DEG C.
Present invention also offers a kind of preparation method such as formula the sulfamide compound shown in I, it comprises the steps: 1. to obtain formula III compound by above-mentioned preparation method; 2., in solvent, under the reflux temperature of 0 DEG C ~ solvent, formula III compound step 1. obtained and alkali react;
Wherein, described X is protonic acid; Described n
2=1 ~ 4, being preferably the integer of 1 ~ 4, is more preferably 1 or 2.
The described preparation method such as formula the sulfamide compound shown in I, preferably comprises the following step: under the reflux temperature of 0 DEG C ~ solvent, is mixed by the solution of formula III compound, react with alkali.
Wherein, described alkali can be organic bases and/or mineral alkali.Described organic bases is preferably one or more in triethylamine, N, N-diisopropyl ethyl amine, dimethylamine and pyridine, is more preferably triethylamine.Described mineral alkali is preferably one or more in ammonia, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, hydrated barta, salt of wormwood, sodium carbonate, sodium bicarbonate and saleratus, is more preferably ammonia and/or sodium hydroxide.Described mineral alkali preferably participates in reaction in form of an aqueous solutions, is more preferably the aqueous solution of ammoniacal liquor and/or sodium hydroxide.The concentration of described ammoniacal liquor can be the concentration of the ammoniacal liquor of this area routine, preferably for volume fraction is the ammoniacal liquor of 25%.The concentration of described aqueous sodium hydroxide solution can be selected by the concentration of the aqueous sodium hydroxide solution of this area routine, is preferably 3mol/L ~ 6mol/L, is more preferably 4mol/L.
The consumption of described alkali is preferably for can neutralize the acid in formula III compound completely, and namely in system, pH is 7.0 ~ 8.0, more preferably for being n with the mol ratio of formula III compound
2: 1, described n
2=1 ~ 4.
Described preferred solvents ground is water and/or organic solvent.Described organic solvent is preferably one or more in methyl alcohol, ethanol, propyl alcohol, tetrahydrofuran (THF), methylene dichloride, Isosorbide-5-Nitrae-dioxane and acetonitrile.The consumption of described solvent is preferably 1mL/g ~ 20mL/g formula III compound, is more preferably 3mL/g ~ 10mL/g formula III compound.
The temperature of described reaction is preferably 0 DEG C ~ 100 DEG C, is more preferably 0 DEG C ~ 30 DEG C.
The process of described reaction is monitored by the pH value measuring reaction system, generally using the pH of reaction system close to time 7.0 (preferably for 7.0 ~ 8.0) as the terminal of reaction.
Aftertreatment purifying formula I also can be carried out after described reaction terminates.Described post-treating method can be the post-treating method of this area routine, and preferably step comprises: the system after reaction being terminated is filtered, and filter residue washes with water, dry.Better step comprises: mix after reaction system concentrating under reduced pressure with water, and filter, filter residue washes with water, dry.The temperature of described drying can be the drying temperature of this area routine, is preferably 40 DEG C ~ 60 DEG C, is more preferably 50 DEG C.The time of described drying can be the time of drying of this area routine, is preferably 6 hours ~ 7 hours, is more preferably 6 hours.The described consumption concentrating the water in mixing with water is afterwards preferably 1mL/g ~ 10mL/g formula III compound, is more preferably 3mL/g formula III compound.
Present invention also offers a kind of intermediate such as formula the sulfamide compound shown in IV,
Wherein, n
2=1 ~ 4, be preferably the integer of 1 ~ 4, better is 1 or 2; Described X is the protonic acid that underpressure distillation can be leaned on to remove, and is preferably hydrogenchloride, trifluoracetic acid, acetic acid, Hydrogen bromide, oxalic acid, tartrate or citric acid; The negative pressure of described underpressure distillation is 15 ~ 30 mmhg, and the temperature of described underpressure distillation is 30 DEG C ~ 60 DEG C.
In the present invention, the preferably reaction scheme preparing formula III compound is as follows:
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can arbitrary combination, obtains the preferred embodiments of the invention.
Those skilled in the art, according to technique scheme, in conjunction with specific embodiments, can realize the present invention without creative work.
Agents useful for same of the present invention and raw material are all commercially.
Positive progressive effect of the present invention is: preparation method's reaction conditions of the present invention is gentle, easy and simple to handle, aftertreatment is easy, productive rate is high, and almost quantitatively (90% ~ 100%) obtains described product and is more suitable for suitability for industrialized production.In addition, the water-soluble of formula III compound of the present invention is obviously better than formula I.
Embodiment
Mode below by embodiment further illustrates the present invention, but does not therefore limit the present invention among described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or selects according to catalogue.
In following each embodiment,
1h-NMR VarianMercury400 nuclear magnetic resonance analyser test, chemical shift represents with δ (ppm); Mass spectrum Agilent1100LC-MS mass spectrograph measures; HPLC is Shimadzu system.
Embodiment 1
Compound 1 (2.3g, 6.5mmol) is dissolved in 40mL methyl alcohol, adds the concentrated hydrochloric acid of 2.0mL36.5%, stir or with ultrasonic oscillation, solid all dissolved.Concentrating under reduced pressure, except desolventizing and excessive aqueous hydrochloric acid, obtains yellow solid residue.Utilize ethyl acetate to pull an oar, filter, obtain 2.77 grams of yellow powdery solid, be hydrochloride IV-a, productive rate 99.6%.This intermediate does not need separation to be directly used in next step.
The hydrogen modal data of compound IV-a:
1h-NMR (400MHz, DMSO-d6): δ 9.135 (s, 1H), 8.126 (s, 1H), 8.114 (s, 1H), 7.92 ~ 7.90 (m, 1H), 7.575.54 (m, 3H), 3.74 (brs, 2HCl), 2.205 (s, 3H), (1.14 s, 9H).It is 100% that HPLC (254nm) records purity.
Embodiment 2
Compound 1 (2.3g, 6.5mmol) is dissolved in 20mL acetic acid, stirs 30 minutes, solid is all dissolved.Concentrating under reduced pressure, removes excessive acetic acid (being also simultaneously solvent), obtains yellow solid residue.Utilize ethyl acetate to pull an oar, filter, obtain yellow powdery solid, be acetate IV-c.2.70 grams, productive rate is 100%.This intermediate does not need separation to be directly used in next step.
The hydrogen modal data of compound IV-c:
1h-NMR (400MHz, DMSO-d6): δ 9.174 (s, 1H), 8.186 (s, 1H), 8.162 (s, 1H), 7.98 ~ 7.90 (m, 1H), 7.62 ~ 7.60 (m, 2H), 7.568 (s, 1H), 3.72 (brs, 1H, CH
3cO
2h), 2.253 (s, 3H), 1.95 (s, 3H), 1.056 (s, 9H); It is 98.5% that HPLC (254nm) records purity.
Embodiment 3
Compound 1 (2.3g, 6.5mmol) is dissolved in 40mL methylene dichloride, adds 10mL trifluoracetic acid, stir or with ultrasonic oscillation, solid all dissolved.Concentrating under reduced pressure, except desolventizing and excessive trifluoracetic acid, obtains yellow solid residue.Utilize ethyl acetate to pull an oar, filter, obtain yellow powdery solid, obtain 3.03 grams of trifluoroacetate IV-b, productive rate 100%.This intermediate does not need separation to be directly used in next step.
The hydrogen modal data of compound IV-b:
1h-NMR (400MHz, DMSO-d6): δ 9.041 (s, 1H), 8.048 (s, 1H), 8.025 (s, 1H), 7.82 ~ 7.78 (m, 1H), 7.50 ~ 7.46 (m, 2H), 7.43 (s, 1H), 4,187 (brs, 2H, 2CF
3cO
2h), 2.115 (s, 3H), 1.056 (s, 9H).It is 100% that HPLC (254nm) records purity.
Embodiment 4
1.36 grams (2.90mmol, 1.0 equivalents) compound IV-b and 555 milligram of (2.90mmol, 1.0 equivalents) 4-(4-methyl isophthalic acid-piperazine) aniline is joined in 5 milliliters of DMFs successively.This mixed system utilizes electric mantle to be heated to 85 DEG C, reacts 6 hours.After reaction terminates, a large amount of white solid is had to separate out; LCMS detection reaction transforms completely.Reaction mixture is cooled, be evaporated to a small amount of thick liquid of residue, filter, filter cake washed with isopropyl alcohol, dry, obtain 1.73 grams of gray solid (the N-tertiary butyl-3-(5-methyl-2-[4-(4-methyl isophthalic acid-piperazine) anilino]-4-aminopyrimidine)-benzsulfamide trifluoroacetate (III-b), productive rate 96%.
The hydrogen modal data of compound III-b:
1h-NMR (400MHz, DMSO-d6): δ 10.12 (brs, 1H, CF
3cO
2h), 9.92 (s, 2H comprise a CF
3cO
2h), 7.98 ~ 7.93 (m, 2H), 7.90 (s, 1H), 7.74 ~ 7.70 (m, 1H), 7.66 (s, 1H), 7.62 ~ 7.54 (m, 1H), 7.45 (s, 1H), 7.35 ~ 7.30 (m, 2H), 7.00 ~ 6.90 (m, 2H), 3.62 ~ 3.50 (m, 4H), 3.25 ~ 3.14 (m, 2H), 2.98 ~ 3.89 (m, 2H), 2.878 (s, 3H), 2.176 (s, 3H), 1.105 (s, 9H); HPLC (254nm); The purity recorded is 97.5%.
Embodiment 5
0.97 gram (2.33mmol, 1.0 equivalents) compound IV-c and 894 milligram of (4.66mmol, 2.0 equivalents) 4-(4-methyl isophthalic acid-piperazine) aniline is joined in 5 milliliters of Virahols successively.This mixed system utilizes oil bath to be heated to 85 DEG C, reacts 6 hours.After reaction terminates, a large amount of white solid is had to separate out; LCMS detection reaction transforms completely.Reaction mixture is cooled, filter, filter cake washed with isopropyl alcohol, dry, obtain 1.23 grams of gray solid (the N-tertiary butyl-3-(5-methyl-2-[4-(4-methyl isophthalic acid-piperazine) anilino]-4-aminopyrimidine)-benzsulfamide acetate (III-c), productive rate 93%.
The hydrogen modal data of compound III-c:
1h-NMR (400MHz, DMSO-d6): δ 8.731 (s, 1H), 8.526 (s, 1H), 8.17 ~ 8.12 (m, 2H), 7.899 (s, 1H), 7.502 (s, 1H), 7.49 ~ 7.45 (m, 4H), 6.84 ~ 6.81 (m, 2H), 3.345 (brs, 5H comprise a CH
3cO
2h), 3.08 ~ 3.00 (m, 4H), 2.288 (s, 3H), 2.122 (s, 3H), 1.915 (s, 3H), 1.127 (s, 9H); The purity that HPLC (254nm) records is 99.0%.
Embodiment 6
1.0 grams (2.33mmol, 1.0 equivalents) compound IV-a and 447 milligram of (2.33mmol, 1.0 equivalents) 4-(4-methyl isophthalic acid-piperazine) aniline is joined in 5 milliliters of Virahols successively.This mixed system utilizes microwave heating to 110 DEG C, reacts 30 minutes.After reaction terminates, a large amount of white solid is had to separate out; LCMS detection reaction transforms completely.Reaction mixture is cooled to room temperature (25 ~ 30 DEG C), filter, filter cake washed with isopropyl alcohol, dry, obtain 1.25 grams of gray solid (the N-tertiary butyl-3-(5-methyl-2-[4-(4-methyl isophthalic acid-piperazine) anilino]-4-aminopyrimidine)-benzenesulfonamide, hydrochloride (III-a), productive rate 92%.
The hydrogen modal data of compound III-a:
1h-NMR (400MHz, DMSO-d6): δ 12.481 (brs, 1H, HCl), 11.014 (s, 1H, HCl), 10.343 (s, 1H), 9.859 (s, 1H), 7.972 (s, 1H), 7.918 ~ 7.912 (m, 2H), 7.702 (d, J=8.0Hz, 1H), 7.634 (s, 1H), 7.59 ~ 7.55 (m, 1H), 7.282 (d, 8.4Hz, 2H), 6.948 (d, 8.4Hz, 2H), 3.760 ~ 3.732 (m, 2H), 3.492 ~ 3.465 (m, 2H), 3.20 ~ 3.05 (m, 4H), 2.805 (s, 3H), 2.176 (s, 3H), 1.30 (s, 9H), it is 100% that HPLC (254nm) records purity.
Embodiment 7
1.5 grams (3.5mmol, 1.5 equivalents) compound IV-a obtained above and 447 milligram of (2.33mmol, 1.0 equivalents) 4-(4-methyl isophthalic acid-piperazine) aniline is joined in 5 milliliters of Virahols successively.This mixed system utilizes oil bath to be heated to 85 DEG C, reacts 8 hours.After reaction terminates, a large amount of white solid is had to separate out; LCMS detection reaction transforms completely.Reaction mixture is cooled, filter, filter cake washed with isopropyl alcohol, dry, obtain 1.30 grams of gray solid (the N-tertiary butyl-3-(5-methyl-2-[4-(4-methyl isophthalic acid-piperazine) anilino]-4-aminopyrimidine)-benzenesulfonamide, hydrochloride (III-a), productive rate 95%.
The hydrogen modal data of compound III-a:
1h-NMR (400MHz, DMSO-d6): δ 12.481 (brs, 1H, HCl), 11.014 (s, 1H, HCl), 10.343 (s, 1H), 9.859 (s, 1H), 7.972 (s, 1H), 7.918 ~ 7.912 (m, 2H), 7.702 (d, J=8.0Hz, 1H), 7.634 (s, 1H), 7.59 ~ 7.55 (m, 1H), 7.282 (d, 8.4Hz, 2H), 6.948 (d, 8.4Hz, 2H), 3.760 ~ 3.732 (m, 2H), 3.492 ~ 3.465 (m, 2H), 3.20 ~ 3.05 (m, 4H), 2.805 (s, 3H), 2.176 (s, 3H), 1.30 (s, 9H), it is 100% that HPLC (254nm) records purity.
Embodiment 8 (preparation of the N-tertiary butyl-3-(5-methyl-2-[4-(4-methyl isophthalic acid-piperazine) anilino]-4-aminopyrimidine)-benzsulfamide (TG101209):
The 1.0 grams of N-tertiary butyl-3-(5-methyl-2-[4-(4-methyl isophthalic acid-piperazine) anilino]-4-aminopyrimidine)-benzenesulfonamide, hydrochloride (III-a) is dissolved in 3mL water (formation settled solution); Under stirring, slowly drip the ammoniacal liquor of 25%, regulate pH=7.0 ~ 8.0.Separate out black solid, filter, dry, obtain free cpds product, 800 milligrams, productive rate 92%.
1it is completely the same that H-NMR spectrogram and United States Patent (USP) WO2007/053452A1 report.
1H-NMR(400MHz，DMSO-d6)：δ8.70(s，1H)，8.51(s，1H)，8.16～8.10(m，2H)，7.89(s，1H)，7.57(s，1H)，7.52～7.46(m，4H)，6.81(d，J＝9.2Hz，2H)，3.02(t，J＝4.8Hz，4H)，2.45(t，J＝4.8Hz，4H)，2.22(s，3H)，2.11(s，3H)，1.12(s，9H)。
LC-MS (214nm): m/z510.1 (M
++ 1); Retention time: 1.570min; Purity (254nm): 98.8%.
Embodiment 9 (preparation of the N-tertiary butyl-3-(5-methyl-2-[4-(4-methyl isophthalic acid-piperazine) anilino]-4-aminopyrimidine)-benzsulfamide (TG101209):
1.0 grams of (1.60mmol) N-tertiary butyl-3-(5-methyl-2-[4-(4-methyl isophthalic acid-piperazine) anilino]-4-aminopyrimidine)-benzsulfamide trifluoroacetate (III-b) is mixed with 10mL methylene dichloride; Under stirring, drip 1.0mL triethylamine; The suspension generated continues stirring 3 hours.Concentrating under reduced pressure steams solvent and excessive triethylamine; In residue, add 3mL water, continue stirring 5 minutes; The black solid suspended is product, and triethylamine hydrochloride is water-soluble; By suspension filtered, dry, obtain 790 milligrams of free cpds products (formula I), productive rate 97%.
1it is completely the same that H-NMR spectrogram and United States Patent (USP) WO2007/053452A1 report.
1H-NMR(400MHz，DMSO-d6)：δ8.70(s，1H)，8.51(s，1H)，8.16～8.10(m，2H)，7.89(s，1H)，7.57(s，1H)，7.52～7.46(m，4H)，6.81(d，J＝9.2Hz，2H)，3.02(t，J＝4.8Hz，4H)，2.45(t，J＝4.8Hz，4H)，2.22(s，3H)，2.11(s，3H)，1.12(s，9H)。
LC-MS (214nm): m/z510.1 (M
++ 1); Retention time: 1.570min; Purity (254nm): 98.8%.
Embodiment 10 (preparation of the N-tertiary butyl-3-(5-methyl-2-[4-(4-methyl isophthalic acid-piperazine) anilino]-4-aminopyrimidine)-benzsulfamide (TG101209):
1.0 grams of (1.76mmol) N-tertiary butyl-3-(5-methyl-2-[4-(4-methyl isophthalic acid-piperazine) anilino]-4-aminopyrimidine)-benzsulfamide acetate (III-c) is dissolved in 3mL water; Under stirring, drip the aqueous sodium hydroxide solution of 1mL4.0N; Continue stirring and separate out black solid after 3 minutes.Filter, filter cake 1mL deionized water wash, heating under vacuum, to 50 DEG C of dryings 6 hours, obtains 808 milligrams of free cpds products (formula I), productive rate 90%.
1it is completely the same that H-NMR spectrogram and United States Patent (USP) WO2007/053452A1 report.
1H-NMR(400MHz，DMSO-d6)：δ8.70(s，1H)，8.51(s，1H)，8.16～8.10(m，2H)，7.89(s，1H)，7.57(s，1H)，7.52～7.46(m，4H)，6.81(d，J＝9.2Hz，2H)，3.02(t，J＝4.8Hz，4H)，2.45(t，J＝4.8Hz，4H)，2.22(s，3H)，2.11(s，3H)，1.12(s，9H)。
LC-MS (214nm): m/z510.1 (M
++ 1); Retention time: 1.570min; Purity (254nm): 98.8%.
Between effect example 1TG101209 and its esters compound, water miscible experimental result contrasts
Between physicochemical property between TG101209 and its esters compound, one of the most obvious character is the solubleness in water.Standard atmospheric pressure, at 25 DEG C, be dissolved in the water completely by the hydrochloride of 10 milligrams of TG101209 (formula I) with 10 milligrams of TG101209 respectively, the water consumption of the two is respectively 160mL and 6.5mL; Namely the solubleness of TG101209 in water is about 0.0625g/L, and the solubleness of its hydrochloride in water is about 1.538g/L.24.6 times that the latter is the former.
Claims (12)
1. such as formula a salt for the sulfamide compound shown in III,
Wherein, described X is hydrogenchloride; n
2be 2.
2. a preparation method for the salt of sulfamide compound, it comprises the following steps: in solvent, and formula IV compound and compound 2 are carried out linked reaction, and temperature of reaction is 35 DEG C ~ 200 DEG C;
Wherein, described n
2be 1 or 2; Described X is one or more in hydrogenchloride, trifluoracetic acid and acetic acid.
3. preparation method as claimed in claim 2, is characterized in that: described solvent is alcohols protic solvent or aprotic polar solvent; Described alcohols protic solvent is one or more in Virahol, methyl alcohol, ethanol, n-propyl alcohol, butanols and primary isoamyl alcohol; Described aprotic polar solvent is one or more in acetonitrile, DMF, N,N-dimethylacetamide and methyl-sulphoxide; Reaction system is reacted in a heated condition.
4. preparation method as claimed in claim 3, is characterized in that: the mode of described heating is oil bath heating, heating in water bath, electric mantle heating or microwave heating.
5. preparation method as claimed in claim 2, is characterized in that: described formula IV compound and the mol ratio of compound 2 are 1.5:1 ~ 0.5:1.
6. preparation method as claimed in claim 3, it is characterized in that: when reacting in a heated condition, the temperature of described reaction is 80 DEG C ~ 150 DEG C.
7. preparation method as claimed in claim 4, is characterized in that: when using microwave heating, the temperature of described reaction is 80 DEG C ~ 120 DEG C; When using the type of heating beyond microwave heating, the temperature of described reaction is 80 DEG C ~ 90 DEG C.
8. preparation method as claimed in claim 2, is characterized in that: described formula IV compound is obtained by following method: in solvent, compound 1 and protonic acid is reacted, production IV compound;
Wherein, n
2be 1 or 2; Described protonic acid and X be organic proton acid and/or inorganic proton sour; Described organic proton acid is trifluoracetic acid or acetic acid; Described inorganic proton acid is hydrogenchloride.
9. preparation method as claimed in claim 8, is characterized in that: described solvent is water and/or polar organic solvent; Described polar organic solvent is polar aprotic solvent and/or polar aprotic solvent; Described polar aprotic solvent is organic alcohol solvent; Described organic alcohol solvent is methyl alcohol and/or ethanol; Described polar aprotic solvent is one or more in tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, methylene dichloride, chloroform and acetonitrile.
10. preparation method as claimed in claim 8, is characterized in that: described compound 1 and the mol ratio of carrying out the protonic acid reacted with it are 1:1.0 ~ 1:2.5.
11. 1 kinds of preparation methods such as formula the sulfamide compound shown in I, is characterized in that comprising the steps: 1. to obtain formula III compound by the preparation method described in any one of claim 2 ~ 10; 2., in solvent, under the reflux temperature of 0 DEG C ~ solvent, formula III compound step 1. obtained and alkali react;
Intermediate IV in the preparation method of the salt of 12. 1 kinds of sulfamide compounds,
Wherein, n
2be 1 or 2; Described X is that organic proton acid and/or inorganic proton are sour; Described organic proton acid is trifluoracetic acid or acetic acid; Described inorganic proton acid is hydrogenchloride.
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| WO2006133411A1 (en) * | 2005-06-08 | 2006-12-14 | Targegen, Inc. | Methods and compositions for the treatment of ocular disorders |
| CN101370792A (en) * | 2005-11-01 | 2009-02-18 | 塔格根公司 | Bi-aryl meta-pyrimidine inhibitors of kinases |
| CN101735201A (en) * | 2009-12-17 | 2010-06-16 | 宁夏康亚药业有限公司 | Preparation method of piribedil |
| CN102153433A (en) * | 2011-02-22 | 2011-08-17 | 上海大学 | N-monosubstituted-alpha-carbonylamide compound and preparation method thereof |
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| WO2006133411A1 (en) * | 2005-06-08 | 2006-12-14 | Targegen, Inc. | Methods and compositions for the treatment of ocular disorders |
| CN101370792A (en) * | 2005-11-01 | 2009-02-18 | 塔格根公司 | Bi-aryl meta-pyrimidine inhibitors of kinases |
| CN101735201A (en) * | 2009-12-17 | 2010-06-16 | 宁夏康亚药业有限公司 | Preparation method of piribedil |
| CN102153433A (en) * | 2011-02-22 | 2011-08-17 | 上海大学 | N-monosubstituted-alpha-carbonylamide compound and preparation method thereof |
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