CN101643463B - 6- methylcoumarin-7-sulfonylurea compound and synthetic method thereof - Google Patents
6- methylcoumarin-7-sulfonylurea compound and synthetic method thereof Download PDFInfo
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- CN101643463B CN101643463B CN2009100342737A CN200910034273A CN101643463B CN 101643463 B CN101643463 B CN 101643463B CN 2009100342737 A CN2009100342737 A CN 2009100342737A CN 200910034273 A CN200910034273 A CN 200910034273A CN 101643463 B CN101643463 B CN 101643463B
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- methylcoumarin
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- sulfonyl urea
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Abstract
The invention discloses a 6-methylcoumarin-7-sulfonylurea compound with the following structural formula and a synthetic method of the compound. Proofed by an initial pharmacological test, the hypoglycemic activity of the 6-methylcoumarin-7-sulfonylurea compound is similar to 6-bit substitution, and the 6-methylcoumarin-7-sulfonylurea compound can be used as a substitution product of a coumarin-6-sulfonylurea compound. The synthetic method of the 6-methylcoumarin-7-sulfonylurea compound is easy and has an industrialization prospect. R is CH2CH2CH3.
Description
Technical field
The present invention relates to 6-Methylcoumarin-7-sulfonyl urea compound and synthetic method thereof.
Background technology
Diabetes be a kind of by heredity or the day after tomorrow pancreatic secretion insufficient insulin or insulin resistant due to chronic disease, its complication comprises cardiovascular pathological changes, renal failure, retinopathy, ulcer of foot, infection and nervous system disorders.Natural compounds tonka bean camphor (I) and derivative thereof are distributed widely in vegitabilia, have multiple physiologically active, as anti-infective, antiviral, anticancer and blood coagulation resisting function.During oral 250mg/kg, normal and alloxan diabetes rats all there is remarkable hypoglycemic activity.Sulfonylurea drugs is one of oral antidiabetic drug of using the earliest, and its mechanism of action is for stimulating β emiocytosis Regular Insulin, and representing medicine is glimepiride.Document [Han Ying, Tu Shuzi, Zhou Weifen, etc. the synthetic and hypoglycemic activity research [J] of tonka bean camphor sulfonyl urea compound, China Medicine University's journal, 2002,33 (2): 93-97; Qi Gang, Tu Shuzi, the synthetic and hypoglycemic activity research [J] of the beautiful .3-bromo of Wang Qiu tonka bean camphor sulfonyl urea compound, China Medicine University's journal, 2005,36 (1): 7-9; ] the utilization principle of hybridization, the pharmacophore sulfonylurea group amalgamation in tonka bean camphor and the sulfonylurea hypoglycemic compound is obtained a series of compounds, but present disclosed document, sulfonylurea group the position of substitution all replaces in the 6-position.
(I) tonka bean camphor (II) glimepiride (Glimepiride)
Summary of the invention
Technical problem to be solved by this invention provides a kind of 6-Methylcoumarin-7-sulfonyl urea compound, this compound has better therapeutic to diabetes, it is to change the female ring of tonka bean camphor with prior art maximum different and goes up sulfonylurea group the position of substitution, it is replaced in the 7-position replace the 6-position to replace.
The technical problem that the present invention also will solve provides the synthetic method of above-mentioned 6-Methylcoumarin-7-sulfonyl urea compound.
For solving the problems of the technologies described above, the technical solution used in the present invention is as follows:
A kind of 6-Methylcoumarin-7-sulfonyl urea compound, its structural formula is:
Wherein,
The synthetic method of above-mentioned 6-Methylcoumarin-7-sulfonyl urea compound comprises the steps:
(1) under the ice-water bath condition 6-Methylcoumarin is joined in the chlorsulfonic acid, the mol ratio of 6-Methylcoumarin and chlorsulfonic acid is 1: 1～5, being stirred to solid under the room temperature condition dissolves fully, 90～95 ℃ are reacted 3～5h down, cooling adds trash ice under the vigorous stirring, and suction filtration gets solid, washing twice gets 6-Methylcoumarin SULPHURYL CHLORIDE crude product;
(2) the 6-Methylcoumarin SULPHURYL CHLORIDE crude product that under the ice-water bath condition step (1) is obtained joins in the strong aqua, the add-on of 6-Methylcoumarin SULPHURYL CHLORIDE crude product is 0.1～1g in every mL strong aqua, stirring at room 7～9 hours, regulate pH value to 6～8, recrystallization gets white powder, is the 6-Methylcoumarin sulphonamide;
(3) triphosgene is added in the chloroform, after the stirring and dissolving, under the ice-water bath condition, drip the chloroformic solution of aminated compounds, aminated compounds and mol ratio triphosgene are 1: 1～4, finish, room temperature reaction 0.5～2h, the reheat 5～7h that refluxes, distill isocyanic ester;
(4) the 6-Methylcoumarin sulphonamide that step (2) is obtained is dissolved in acetone, adds K
2CO
3Post-heating backflow 1～2h, 6-Methylcoumarin sulphonamide and K
2CO
3Mol ratio be 1: 1～6, drip the acetone soln of the isocyanic ester that step (3) obtains again, finish the 5～7h that refluxes, cooling, filter, filter cake is dissolved in water, and acidifying pH value to 1～2 have solid to produce, filter, be washed with water to neutrality, dry 6-Methylcoumarin-7-sulfonyl urea compound.
In the step (1), described vigorous stirring rotating speed is 100～1000r/min.
In the step (1), the add-on of trash ice is 2～5 times of 6-Methylcoumarin weight.
In the step (2), the concentration of strong aqua is 10～28% (w/w).
In the step (3), the add-on of triphosgene is 5～10mmol in every mL chloroform.
In the step (3), described aminated compounds is 2-aminotoluene, 3-monomethylaniline, 4-monomethylaniline, 23 dimethyl aniline, benzyl amine or n-propyl amine.
In the step (3), the chloroformic solution of described aminated compounds, its concentration is 2～10mmol/L.
In the step (4), the 6-Methylcoumarin sulphonamide is dissolved in acetone, and concentration is 0.1～0.5mmol/L.
In the step (4), the acetone soln of isocyanic ester, concentration is 0.3～1.5mmol/L.
The synthetic route of 6-Methylcoumarin-7-sulfonyl urea compound is as follows:
Beneficial effect: 6-Methylcoumarin of the present invention-7-sulfonyl urea compound, find that through preliminary pharmacological tests the effect of its hypoglycemic activity and the replacement of 6-position is suitable, can be used as the replacement product of tonka bean camphor-6-sulfonyl urea compound.The synthetic method of 6-Methylcoumarin of the present invention-7-sulfonyl urea compound is simple, has industrialization prospect.
Embodiment
According to following embodiment, the present invention may be better understood.Yet, those skilled in the art will readily understand that the described concrete material proportion of embodiment, processing condition and result thereof only are used to illustrate the present invention, and should also can not limit the present invention described in detail in claims.
Embodiment 1:6-methylcoumarin SULPHURYL CHLORIDE (2)
Under ice-water bath, 10g 6-Methylcoumarin (1) (0.06mol) is joined in the 9mL chlorsulfonic acid (0.15mol), holding temperature is lower than 10 ℃, finish, stirring at room is dissolved fully to solid, and reheat to 90～95 ℃ continuation reaction 4h is cooled to room temperature, (800r/min) inclines to the 20g trash ice under the vigorous stirring, suction filtration gets solid, and washing twice gets 6-Methylcoumarin SULPHURYL CHLORIDE crude product (2) 16g and is directly used in the next step.
Embodiment 2:6-methylcoumarin sulphonamide (3)
Gained 6-Methylcoumarin SULPHURYL CHLORIDE crude product (2) 16g adds in frozen water refrigerative 15mL 28% strong aqua, stirring at room 8h regulates pH to neutral with dilute hydrochloric acid, and the water recrystallization gets white powder 2.30g and is 6-Methylcoumarin sulphonamide (3), yield 16%, mp.245～247 ℃.ESI-MS：262[M+Na]
+
Embodiment 3: the synthetic logical method of isocyanic ester
12g triphosgene (0.40mol) is dissolved in the 50mL chloroform, after the stirring and dissolving, the ice bath cooling drips the chloroformic solution of the corresponding aminated compounds of 10mL (0.02moL) down, aminated compounds described here is 2-aminotoluene, 3-monomethylaniline, 4-monomethylaniline, 23 dimethyl aniline, benzyl amine or n-propyl amine, finish, room temperature reaction 1h, reheat backflow 6h, distill corresponding isocyanate.
Embodiment 4:N-(6-Methylcoumarin-7-alkylsulfonyl)-N '-(3-aminomethyl phenyl) urea (4)
(1g 3.29mmol) mixes with acetone 20mL, adds K with 6-Methylcoumarin sulphonamide (3)
2CO
3(1.12g; 8.11mmol) post-heating backflow 1h, drip the acetone soln (0.5mmol/L) of 3-methylbenzene isocyanic ester (3.62mmol) again, finish backflow 6h; cooling; filter, filter cake adds water 20mL dissolving, with about concentrated acid acidifying pH to 1; there is solid to produce; filter, be washed with water to neutrality, dry corresponding product N-(6-Methylcoumarin-7-alkylsulfonyl)-N '-(3-aminomethyl phenyl) urea (4).Other gets an amount of product and separates through silicagel column, is that developping agent launches with ethyl acetate-sherwood oil (1: 4), obtains pure product and is used for analyzing.
Yield: 54%, mp.126～128 ℃.HR-ESI-MS：373.0851(M+1)(FW.373.0852)。
1HNMR：2.15(3H，s，-CH
3)，2.39(3H，s，-CH
3)，6.43～6.53(1H，m，ArH)，6.90～6.95(1H，t，ArH)，7.14～7.16(1H，d，ArH)，7.28(1H，s，ArH)，7.52(1H，s，ArH)，7.87(1H，s，ArH)，7.98～8.01(1H，d，ArH)，8.41(1H，s，ArH)
Embodiment 5:N-(6-Methylcoumarin-7-alkylsulfonyl)-N '-(4-aminomethyl phenyl) urea (5)
With 6-Methylcoumarin sulphonamide (3) and 4-methylbenzene isocyanate reaction, operation gets N-(6-Methylcoumarin-7-alkylsulfonyl)-N '-(4-aminomethyl phenyl) urea (5) with example 4.
Yield: 47%, mp.108～110 ℃.
IR(KBr)vcm
-1：3370，1739，1646，1604，1538，1350，1145
ESI-MS：371(M-1)
1HNMR：2.15(3H，s，-CH
3)，2.39(3H，s，-CH
3)，6.46～6.52(1H，t，ArH)，6.86～6.91(1H，t，ArH)，7.26～7.29(2H，dd，ArH)，7.50～7.58(1H，d，ArH)，7.75(1H，s，ArH)，7.98～8.03(1H，m，ArH)，8.34～8.42(1H，d，ArH)
Embodiment 6:N-(6-Methylcoumarin-7-alkylsulfonyl)-N '-(2-aminomethyl phenyl) urea (6)
With 6-Methylcoumarin sulphonamide (3) and 2-methylbenzene isocyanate reaction, operation gets N-(6-Methylcoumarin-7-alkylsulfonyl)-N '-(2-aminomethyl phenyl) urea (6) with example 4.
Yield: 50%, mp.106～108 ℃.
IR(KBr)vcm
-1：3368，3069，1731，1614，1539，1347，1145
ESI-MS：371(M-1)HR-ESI-MS：371.0730(M-1)(FW.371.0696)
1HNMR：2.12(3H，s，-CH
3)，2.43(3H，s，-CH
3)，6.59～6.62(1H，d，ArH)，6.93～7.14(3H，m，ArH)，7.50～7.53(1H，d，ArH)，7.84(1H，s，ArH)，7.95(1H，s，ArH)，8.07～8.14(2H，m，ArH)，11.16(1H，br，-NH)
Embodiment 7:N-(6-Methylcoumarin-7-alkylsulfonyl)-N '-(2, the 3-3,5-dimethylphenyl) urea (7)
With 6-Methylcoumarin sulphonamide (3) and 2,3-dimethyl benzene isocyanate reaction, operation gets N-(6-Methylcoumarin-7-alkylsulfonyl)-N '-(2, the 3-3,5-dimethylphenyl) urea (7) with example 4.
Yield: 42%, mp.202～204 ℃.
IR(KBr)vcm
-1：3368，3065，1728，1626，1610，1552，1350，1142
HR-ESI-MS：385.0836(M-1)(FW.385.0852)
1HNMR：1.99(3H，s，-CH
3)，2.19(3H，s，-CH
3)，2.41(3H，s，-CH
3)，6.55～6.61(1H，t，ArH)，6.83～6.92(2H，m，ArH)，7.34(1H，s，ArH)，7.75(1H，s，ArH)，7.91(1H，s，ArH)，8.05～8.10(H，m，ArH)
Embodiment 8:N-(6-Methylcoumarin-7-alkylsulfonyl)-N '-benzylurea (8)
With 6-Methylcoumarin sulphonamide (3) and the reaction of benzyl isocyanate ester, operation gets N-(6-Methylcoumarin-7-alkylsulfonyl)-N '-benzylurea (8) with example 4.
Yield: 45%, mp.96～98 ℃.
IR(KBr)vcm
-1：3372，3063，1732，1638，1604，1555，1342，1149
ESI-MS：371(M-1)
1HNMR：2.41(3H，s，-CH
3)，4.22～4.24(2H，s，-NCH
2)，6.59～6.63(1H，d，ArH)，6.86(1H，br-NH)，7.09～7.31(5H，m，ArH)，7.79(1H，s，ArH)，7.89(1H，s，ArH)，8.08～8.11(1H，d，ArH)
Embodiment 9:N-(6-Methylcoumarin-7-alkylsulfonyl)-N '-n-propyl urea (9)
With 6-Methylcoumarin sulphonamide (3) and propyl group isocyanate reaction, operation gets N-(6-Methylcoumarin-7-alkylsulfonyl)-N '-n-propyl urea (9) with example 4.
Yield: 43%, mp.140～143 ℃.
IR(KBr)vcm
-1：3350，3095，1746，1666，1625，1555，1344，1145
ESI-MS：323(M-1)
1HNMR：0.71～0.76(3H，s，-CH
3)，1.14～1.33(2H，m，-CH
2-)，2.41(3H，s，-CH
3)，2.85～2.89(2H，t，-NCH
2)，6.28(1H，br，-NH)，6.55～6.58(1H，d，ArH)，7.75(1H，s，ArH)，7.87(1H，s，ArH)，8.06～8.09(1H，d，ArH)
Embodiment 10: the blood sugar reducing function of target compound
Influence to normal mouse blood sugar: 60 mouse are divided into 6 groups at random by body weight, 10 every group.The dosage of target compound (4 to 9) is 50mg/kg, is configured to suspension with 0.5%CMC-Na before the administration and irritates stomach for animal, and positive control is glyburide 50mg/kg, and negative control is the 0.5%CMC-Na of equivalent.2h and 4h measure the blood sugar concentration of each mouse respectively behind the gastric infusion.Method is as follows: get blood with the capillary glass-tube from the mouse orbit rear vein beard, behind the centrifugal 10min of 3000r/min, get serum 10mL, measure glucose concn with blood sugar quantitative determination process (GOD-PAP method), the results are shown in Table 1.
Table 1 6-Methylcoumarin-7-solsonylurea compounds to the influence of blood sugar (x ± s, n=10)
**p＜0.01，
*p＜0.05(compared?with?0.5％CMC-Na)
The hypoglycemic experimental result shows that compound (6) all has the obvious functions of blood sugar effect at 2h and 4h to normal mouse, compare P＜0.01 with the 0.5%CMC-Na group, reason may be that the preferred conformation of tonka bean camphor sulfonylurea active compound generally is " U " type, and the ortho position methyl on the urea groups substituting group phenyl ring of compound 6 helps such structure formation, causes its activity higher; In addition, compound (7) also has hypoglycemic activity, P＜0.05 when 2h.Compound (6) and glyburide group are compared, blood sugar decreasing effect is suitable, but the trend that prolongs action time is arranged, and the prospect of further research is arranged, hypoglycemic activity and document [Zhou Weifen with all coumarin-7-sulfonyl urea compounds, Wang Qiujuan, Han Ying, etc. the hypoglycemic activity research [J] of tonka bean camphor sulfonyl urea compound, China Medicine University's journal, 2003,34 (2): 160-162] hypoglycemic activity of tonka bean camphor-6-sulfonyl urea compound contrast finds that activity is suitable substantially.
Claims (10)
1. 6-Methylcoumarin-7-sulfonyl urea compound, its structural formula is:
Wherein, R is
2. the synthetic method of the described 6-Methylcoumarin of claim 1-7-sulfonyl urea compound is characterized in that this method comprises the steps:
(1) under the ice-water bath condition 6-Methylcoumarin is joined in the chlorsulfonic acid, the mol ratio of 6-Methylcoumarin and chlorsulfonic acid is 1: 1～5, being stirred to solid under the room temperature condition dissolves fully, 90～95 ℃ are reacted 3～5h down, cooling adds trash ice under the vigorous stirring, and suction filtration gets solid, washing twice gets 6-Methylcoumarin SULPHURYL CHLORIDE crude product;
(2) the 6-Methylcoumarin SULPHURYL CHLORIDE crude product that under the ice-water bath condition step (1) is obtained joins in the strong aqua, the add-on of 6-Methylcoumarin SULPHURYL CHLORIDE crude product is 0.1～1g in every mL strong aqua, stirring at room 7～9 hours, regulate pH value to 6～8, recrystallization gets white powder, is the 6-Methylcoumarin sulphonamide;
(3) triphosgene is added in the chloroform, after the stirring and dissolving, under the ice-water bath condition, drip the chloroformic solution of aminated compounds, aminated compounds and mol ratio triphosgene are 1: 1～4, finish, room temperature reaction 0.5～2h, the reheat 5～7h that refluxes, distill isocyanic ester;
(4) the 6-Methylcoumarin sulphonamide that step (2) is obtained is dissolved in acetone, adds K
2CO
3Post-heating backflow 1～2h, 6-Methylcoumarin sulphonamide and K
2CO
3Mol ratio be 1: 1～6, drip the acetone soln of the isocyanic ester that step (3) obtains again, finish the 5～7h that refluxes, cooling, filter, filter cake is dissolved in water, and acidifying pH value to 1～2 have solid to produce, filter, be washed with water to neutrality, dry 6-Methylcoumarin-7-sulfonyl urea compound.
3. the synthetic method of 6-Methylcoumarin according to claim 2-7-sulfonyl urea compound is characterized in that in the step (1), described vigorous stirring rotating speed is 100～1000r/min.
4. the synthetic method of 6-Methylcoumarin according to claim 2-7-sulfonyl urea compound is characterized in that in the step (1) that the add-on of trash ice is 2～5 times of 6-Methylcoumarin weight.
5. the synthetic method of 6-Methylcoumarin according to claim 2-7-sulfonyl urea compound is characterized in that in the step (2) that the concentration of strong aqua is 10～28% (w/w).
6. the synthetic method of 6-Methylcoumarin according to claim 2-7-sulfonyl urea compound is characterized in that in the step (3), the add-on of triphosgene is 5～10mmol in every mL chloroform.
7. the synthetic method of 6-Methylcoumarin according to claim 2-7-sulfonyl urea compound is characterized in that in the step (3), described aminated compounds is a 2-aminotoluene.
8. according to the synthetic method of claim 2 or 7 described 6-Methylcoumarin-7-sulfonyl urea compounds, it is characterized in that in the step (3), the chloroformic solution of described aminated compounds, its concentration is 2～10mmol/L.
9. the synthetic method of 6-Methylcoumarin according to claim 2-7-sulfonyl urea compound is characterized in that the 6-Methylcoumarin sulphonamide is dissolved in acetone in the step (4), and concentration is 0.1～0.5mmol/L.
10. the synthetic method of 6-Methylcoumarin according to claim 2-7-sulfonyl urea compound is characterized in that in the step (4), the acetone soln of isocyanic ester, and concentration is 0.3～1.5mmo/L.
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Non-Patent Citations (8)
| Title |
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| .香豆素磺酰脲类化合物的合成及其降血糖活性研究.《中国药科大学学报》.2002,第33卷(第2期),93-97. |
| 周卫芬 |
| 屠树滋 |
| 王秋娟 |
| 祁刚,屠树滋,王秋娟,马琳.多取代香豆素磺酰脲类化合物的合成及其降血糖活性研究.《中国药物化学杂志》.2004,第14卷(第6期),第331-334页. * |
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| 韩莹;屠树滋;周卫芬;王秋娟;.香豆素磺酰脲类化合物的合成及其降血糖活性研究.《中国药科大学学报》.2002,第33卷(第2期),93-97. * |
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