CN1298720C - Sinomenine derivative with C cycle connected to penetabasic heterocycle and synthesizing method - Google Patents
Sinomenine derivative with C cycle connected to penetabasic heterocycle and synthesizing method Download PDFInfo
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- CN1298720C CN1298720C CNB2005100244789A CN200510024478A CN1298720C CN 1298720 C CN1298720 C CN 1298720C CN B2005100244789 A CNB2005100244789 A CN B2005100244789A CN 200510024478 A CN200510024478 A CN 200510024478A CN 1298720 C CN1298720 C CN 1298720C
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Abstract
The present invention relates to a sinomenine derivative with the ring C connected with 5-membered heterocycles and a synthetic method of the sinomenine derivative. The structural formula of the sinomenine derivative is given by eq. 1, wherein R<1> is equal to OH, R<2> is equal to H, or R<1> and R<2> are equal to what is given by eq. 2; R<3> and R<4> are equal to alkyls or unsaturated hydrocarbons containing 1 to 14 carbon atoms; R <5> is equal to H, O, S, alkyl containing 1 to 10 carbon atoms, which is given by eq. 3, or a pentahydric or hexahydric aromaticring, a nitrogen heterocycle, an oxygen heterocycle or a sulfur heterocycle with at most three substituents or without substituents. The substituents are hydrocarbyls containing 1 to 10 carbon atoms, halogen, alkyls containing 1 to 4 carbon atoms, fluoroalkyl group, nitro group, nitrile group, methoxy group or hydroxyl group. The symbol-> stands for a double bond or a single bond. The synthetic method has the characteristic of mild, simple and specific reaction condition, and is suitable for commercial process.
Description
Technical field
The present invention relates to the Sinomenine derivate and the synthetic method of C cycle connected to penetabasic heterocycle, promptly the C ring synthetic C ring of hydrolysate that is connected with Sinomenine derivate, the aldehyde with dissimilar, ammonium acetate and the tuduranine of imidazole ring or tetrahydroglyoxaline (sulphur) ketone ring is connected with the Sinomenine derivate of imidazole ring and is connected with the method for the Sinomenine derivate of tetrahydroglyoxaline (sulphur) ketone with carbamide compounds and the synthetic C ring of tuduranine hydrolysate.
Background technology
Traditional Chinese medicine is the basic substance that cures the sickness to save the patient, ensures people's health, is that the very rich experience that Chinese working people struggles with disease is for a long time summed up, and the prosperity of the Chinese nation is had great contribution.
Along with the development of society and the change of human diseases spectrum, medical model changes the pattern that prevention, health care, treatment, rehabilitation combine into by simple disease treatment, various alternative medicines and traditional medicine are when playing a significant role, the cry of human " back to nature returns green " is also more and more higher.Chinese materia medica is then emphasized the man and nature combination, has just in time met the trend that people faced the future, pursued green consumption, and paying attention to traditional Chinese medicine has become important trend, and traditional Chinese medicine is subjected to more concern day by day in the whole world.Not only the Asian countries people are to the acceptance level height (reach 49% as Japan, Singapore reaches 45%) of traditional Chinese medicine, and developed countries such as America and Europe are also improving constantly the acceptance level of traditional Chinese medicine.
Under the drive of demand, world market enlarges year by year, and annual speed increase with 10-20%.In recent years, except that Southeast Asian countries and regional traditional Chinese medicine still kept vigorous demand, North America, market, West Europe were also active day by day, and African, Arabic traditional Chinese medicine market is also enlarging gradually.Current, the Chinese medicine development of science and technology presents the trend that makes new advances, traditional Chinese medicine changes to modern Chinese herbal medicine, formally propose by State Scientific and Technological Commission in July, 1996 and advocate " modernization of Chinese medicine scientific and technological industry action plan ", deeply launch at present and implement, thereby promoted China's traditional Chinese medicine to develop to higher, renewal, more deep level, its aim is by utilization modern science and technology means, and this has the representative subject of China's national cultural feature most and the most characteristic conventional industries develop to modernization, industrialization, internationalization direction to promote Chinese materia medica.Be accompanied by developing rapidly of the modernization of Chinese medicine, various advanced persons' modern science and technology have been widely used in each link of traditional Chinese medicine research, exploitation, production.Modern preparation technique has been widely used in the transformation of traditional Chinese medicine formulation.Chinese medicine preparation is by the ball in past, diffusing, cream, red to modern preparation developments such as controlled release, slowly-releasing, targets; Various advanced persons' extraction, isolation technique are more and more general in Chinese medicine is produced, and the modernization that Chinese medicine is produced is more and more higher.Chinese medicine is just more and more tightr with combining of modern science and technology, and traditional Chinese medicine changes (Chinese the 8th phase of complex clinical medicine magazine) to modern Chinese herbal medicine.Herbal medicine is natural combinatorial chemical library, exists about millions of kinds of compounds in thousands of kinds of herbal medicine, and the structure type of these compounds has almost been included the structure type of all compounds, is the most intact natural combinatorial chemical library.At present through extraction, separation, purifying, determine that the medicinal herb components of structure has about 10000 kinds.The Chinese medicinal ingredients that cheaply is easy to get is carried out structural modification and transformation, and medicine is the road of a very feasible Chinese medicine in-depth development thereby obtain more efficiently.The present invention has carried out structure of modification to tuduranine exactly, the Sinomenine derivate of, low toxicity more efficient in the hope of obtaining.
Caulis Sinomenii is a common Chinese medicine, and " Caulis Sinomenii " title beginning sees Song's " figure is through book on Chinese herbal medicine " and Compendium of Material Medica all has than write up.The wind-damp dispelling the meridian dredging is arranged, pain-relieving functions.Be used for diseases such as rheumatic and rheumatoid arthritis, limbs pain is numb and damage that sore swells.Mainly be distributed in provinces such as Shaanxi, Henan, Hubei, Jiangsu, Anhui, Zhejiang, Jiangxi, Fujian.Stem of Orientoine stem glue and root contain tuduranine (sinomenine), sinoacutine (sinoacutine), disinomenine (disinomenine), ethyl tuduranine (ethylsinomenine, be isosinomenine isosinomenine), tetrahydrochysene epiberberine sinactine), acutumine (acutumine), acutumide (acutumidine), soil rattan alkali (tuduranine), magnoline (magnoflorine), other contains the stepharine (stepherine) of trace, michelalbine (michelalbine), dl-syringaresinol (dl-syringaresinol) and β-Gu Zaichun, Stigmasterol etc.
Tuduranine sinoacutine acutumine R=CH
3
Acutumide R=H
Tuduranine (sinomenine) is to separate the isoquinoline alkaloid that obtains from Stem of Orientoine (Sinomenium acutum).Because the most biologically active of alkaloid compound, has complicated structure again, so alkaloid is attracting organic chemists' interest and lasting (searching) on the net always.Tuduranine has physiologically actives such as anti-inflammatory, immunity, analgesia, step-down, anti-arrhythmia.Various rheumatosis such as preparations such as existing ZHENGQINGFENGTONGNING PIAN, sinomenine hydrochloride injection liquid, hair sinomenium acutum total alkali sheet are applied to clinical, the treatment rheumatoid arthritis and heart disorder obtain better curative effect (Liu Qiang, etc., herbal medicine, 1997,28 (4): 247-249).But its dosage is bigger than normal, by irritated side effect.Therefore, this patent has carried out structural modification and has optimized research tuduranine, new class Sinomenine derivate efficient to seek, low toxicity.
The tuduranine hydrochloride can be in 10% hydrochloric acid obtaining of hydrolysis and thing 1 (Acta Pharmaceutica Sinica ActaPharmaceutica Sinica 2004,39 (3); 180-183), chemical equation is as follows:
Tuduranine hydrochloride 1
The C ring of the hydrolysate of tuduranine (compound 1) has α-diketone structure, and α-diketone, aldehyde and ammonium acetate condensation are synthetic the most frequently used method (Grimmett, the M.R.In Comprehensive heterocyclieChemistry of imidazole ring; Katritzky, A.R., Rees, C.W., Eds.; Pergamon:New York, 1984; Vol.5 p457), chemical equation is as follows:
Simultaneously, α-diketone and urea, thiocarbamide can generate tetrahydroglyoxaline-2-ketone (imidazolin-2-oneor imidazolin-2-thione) or imidazoline-2-sulfur-one with α-two reactive ketone, the document points out that simultaneously the nitrogen substituting thioureido also can generate the imidazoline-2-sulfur-one that multi-substituent is arranged with α-two reactive ketone, (Grimmett, M.R.In Comprehensiveheterocyclic Chemistry; Katritzky, A.R., Rees, C.W., Eds.; Pergamon:NewYork, 1984; Vol.5p478-482), chemical equation is as follows:
X＝O、S
Like this, hydrolysate (compound 1) with tuduranine is guide's thing, utilizes above-mentioned two kinds of methods, can expect to obtain the new Sinomenine derivate of two classes, the one, be connected with the Sinomenine derivate of imidazole ring, the one, be connected with the Sinomenine derivate of tetrahydroglyoxaline (sulphur) ketone ring.
Summary of the invention
The object of the invention just provides a kind of C ring and connects the Sinomenine derivate that has the five-membered ring of different substituents
Another object of the present invention provides the method for the above-mentioned Sinomenine derivate of preparation.
Sinomenine derivate of the present invention has following structure:
R wherein
1=OH, R
2=H, or R
1With
R
3And R
4=C
1-14Alkyl or unsaturated hydrocarbons; R
5=H, O, S, C
1～10Alkyl,
Have one～three substituting group or be not with substituent five yuan or hexavalent aromatic ring, nitrogen heterocyclic ring, oxygen heterocyclic ring or sulfur heterocyclic ring, described substituting group is C
1～10Alkyl, halogen, C
1～4Alkyl or contain fluoroalkyl, nitro, itrile group, methoxyl group or hydroxyl, two keys of → representative or singly-bound.
Compound of the present invention can also further describe the compound into following structure:
R wherein
1=OH, R
2=H, or R
1With
R
3And R
4=C
1-14Alkyl or unsaturated hydrocarbons, R
6=H, C
1～10Alkyl,
Have one～three substituting group or be not with substituent five yuan or hexavalent aromatic ring, nitrogen heterocyclic ring, oxygen heterocyclic ring or sulfur heterocyclic ring, described substituting group is C
1～10Alkyl, halogen, C
1～4Alkyl or contain fluoroalkyl, nitro, itrile group, methoxyl group or hydroxyl, X=O or S.
Compound of the present invention can also be example with the following compounds:
The present invention is connected with the Sinomenine derivate preparation method of five-membered ring, in organic solvent and under room temperature～reflux temperature, adopts two kinds of methods of (1) or (2) to make respectively:
(1). the hydrolysate of tuduranine, aldehyde and ammonium acetate reacted 1～20 hour; The hydrolysate of described tuduranine, aldehyde and ammonium acetate mol ratio are 1: 1～2: 1～20;
(2). the hydrolysate of tuduranine, urea or thiocarbamide and organic acid or inorganic acid reaction time are 5-20 hour, and the mol ratio of the hydrolysate of described tuduranine, urea or thiocarbamide and organic acid or mineral acid is 1: 2～3: 3～5.
Chemical equation is as follows respectively:
Temperature of reaction is relevant with the reaction times, the temperature of reaction height, and speed of response is fast.When the hydrolysate of tuduranine, ammonium acetate and aldehyde reaction, the proposal reactions temperature is a room temperature to 70 ℃, and the reaction times is 1～20 hour.When hydrolysate, urea or the thiocarbamide of tuduranine and organic acid or inorganic acid reaction, the proposal reactions temperature is a reflux temperature, and the reaction times is 5-20 hour.
The hydrolysate structural formula of described tuduranine is as follows:
The structural formula of described urea or thiocarbamide is as follows:
Described aldehyde molecular formula is R
6CHO, wherein R
1, R
2, R
3, R
4And R
6As mentioned above.
The organic solvent of above indication is methyl alcohol, ethanol, different third pure, the trimethyl carbinol, methylene dichloride, chloroform, 1,2-ethylene dichloride, tetracol phenixin, ether, tetrahydrofuran (THF), benzene,toluene,xylene, acetone, butanone, acetonitrile, N, dinethylformamide (DMF) or methyl-sulphoxide (DMSO).
The organic acid of above indication is formic acid, acetate, trifluoracetic acid or oxalic acid; Mineral acid is hydrochloric acid or sulfuric acid.
Method of the present invention successfully connects the C of tuduranine ring and has substituting group or not with substituent imidazole ring or tetrahydroglyoxaline (sulphur) ketone ring the time, also tuduranine can be converted into the compound with (+) morphine structure, and two steps transformed and can one pot finish; Gained compound structure novelty is the target product that well carries out biological activity test; This reaction also has reaction conditions gentleness, easy and single-minded characteristics, and can be used for suitability for industrialized production.
Embodiment
To help reason to connect by following embodiment and separate the present invention, but can not limit content of the present invention.
Embodiment 1
3.04g ammonium acetate (39mmol) is dissolved in the 30ml ethanol, add 1.24g compound 1 (3.94mmol), then add 0.63g phenyl aldehyde (5.9mmol), stirring at room 10 hours, concentrate, add 30ml water and 30ml methylene dichloride and in separating funnel, shake layering, remove organic phase, with water alkalize to the pH value for 8-9, use methylene dichloride (3 * 30) extraction then, merge organic interdependent water, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, the evaporating column chromatography gets the 1.0g product, productive rate 79%.
1H?NMR(CDCl
3∶CD
3OD＝10∶1，300MHz)：7.72(2H，m)，7.34(2H，m)，7.26(1H，m)，6.62(2H，2d，J＝8.4)4.79(1H，d，J＝15.6)，3.77(3H，s)，3.09(1H，m)，2.98(2H，m)，2.49(5H，m)2.42(3H，s)，2.19(1H，dt，J＝3.0，12.3)，1.99(1H，m)，1.84(1H，dt，J＝4.8，12.9)。
IR(KBr)：3508，2909，2840，1623，1602，1481，1458，1437，1400，1278，1225，1105，1063，1054，1022，856，771，701，695cm
-1。
MS(ESI，m/z)：402.4(M+H
+)。
Embodiment 2
2.94g ammonium acetate (36mmol) is dissolved in 30ml ethanol or the ether, add 1.15g compound 1 (3.6mmol), then add 032g propionic aldehyde (5.5mmol), stirring at room 12 hours, concentrate, add 30ml water and 30ml methylene dichloride and in separating funnel, shake layering, remove organic phase, with water alkalize to the pH value for 8-9, use methylene dichloride (3 * 30) extraction then, merge organic phase, merge organic interdependent water, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, the evaporating column chromatography gets the 0.84g product, productive rate 75%.
1H?NMR(CDCl
3∶CD
3OD＝10∶1，300MHz)：6.62(2H，2d，J＝8.4)，4.69(1H，d，J＝15.9)，3.79(3H，s)，3.03(3H，m)，2.59(2H，q，J＝7.5)，2.48(2H，m)，2.40(3H，s)，2.38(2H，m)，2.23(2H，m)，2.00(1H.m)，1.20(3H，t，J＝7.5)，1.81(1H，dt，J＝4.5，12.9)。
IR(KBr)：3516，2913，2892，1631，1606，1478，1437，1342，1275，1227，1143，1103，1060，1053，1024，791，754cm
-1。
MS(ESI，m/z)：354.4(M+H
+)。
Embodiment 3
2.45g ammonium acetate (31mmol) is dissolved in 25ml chloroform or the ethanol, add 1.0g compound 1 (3.1mmol), then add 0.67g 4-chlorobenzaldehyde (4.8mmol), stirring at room 6 hours, concentrate, add 30ml water and 30ml methylene dichloride and in separating funnel, shake layering, remove organic phase, with water alkalize to the pH value for 8-9, use methylene dichloride (3 * 30) extraction then, merge organic phase, merge organic interdependent water, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, the evaporating column chromatography gets the 0.84g product, productive rate 75%.
1H?NMR(CDCl
3，300MHz)：10.44(1H，Brs.)，7.63(2H，d，J＝9.0)，7.20(2H，d，J＝9.0)，6.62(2H，2d，J＝8.4)，5.91(1H，brs.)，4.71(1H，d，J＝16.2)，3.76(3H，s)，3.06(2H，m)，2.86(1H，m)，2.59(4H，m)，2.42(3H，s)，2.32(1H，m)，2.14(1H，dt，J＝3.0，12.3)，1.95(1H，m)，1.84(1H，dt，J＝4.5，12.3)。
IR(KBr)：3508，2907，2840，1621，1526，1481，1437，1380，1279，1225，1104，1064，1053，1053，834，754cm
-1。
MS(ESI，m/z)：436.2(M+H
+)。
Embodiment 4
2.45g ammonium acetate (31mmol) is dissolved in the 25ml benzene, add 1.0g compound 1 (3.1mmol), then add 0.88g 2-bromobenzaldehyde (4.8mmol), 70 ℃ were stirred 1 hour, concentrate, add 30ml water and 30ml methylene dichloride and in separating funnel, shake layering, remove organic phase, with water alkalize to the pH value for 8-9, use methylene dichloride (3 * 30) extraction then, merge organic phase, merge organic interdependent water, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, the evaporating column chromatography gets the 1.2g product, productive rate 84%.
1H?NMR(CDCl
3，300MHz)：9.95(1H，Brs.)，8.16(1H，d，J＝1.5)，7.55(1H，d，J＝8.1)，7.30(1H，dt，J＝1.5，7.5)，7.10(1H，dt，J＝1.5，7.5)，6.63(2H，2d，J＝8.7)，6.05(1H，brs.)，4.78(1H，d，J＝16.2)，3.78(3H，s)，3.16(1H，m)，3.02(2H，m)，2.58(4H，m)，2.48(3H，s)2.40?1H，m)，2.10(1H，dt，J＝3.3，11.7)，2.01(1H，m)1.93(1H，dt，J＝4.5，12.6)。
IR(KBr)：3504，3432，2908，2841，1616，1481，1437，1278，1225，1063，1052，1025，983，856，757cm
-1。
MS(ESI，m/z)：480.1(M+H
+)。
Embodiment 5
2.45g ammonium acetate (31mmol) is dissolved in the 25ml ethanol, add 1.0g compound 1 (3.1mmol), then add 0.74g 1-naphthaldehyde (4.8mmol), stirring at room 20 hours, concentrate, add 30ml water and 30ml methylene dichloride and in separating funnel, shake layering, remove organic phase, with water alkalize to the pH value for 8-9, use methylene dichloride (3 * 30) extraction then, merge organic phase, merge organic interdependent water, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, the evaporating column chromatography gets the 1.07g product, productive rate 75%.
1H?NMR(CDCl
3，300MHz)：8.61(1H，d，J＝9.0)，7.75(2H.m)，7.42(4H，m)，6.63(2H，2d，J＝8.1)，6.14(1H，brs.)，4.74(1H，d，J＝15.9)，3.71(3H，s)，2.96(3H，m)，2.47(3H，s)，2.41(5H，m)，2.17(1H，dt，J＝2.7，9.6)，1.94(1H，m)，1.85(1H，dt，J＝4.5，13.2)。
IR(KBr)：3502，2907，2840，1618，1481，1437，1401，1380，1278，1225，1063，1053，802，776，753cm
-1。
MS(ESI，m/z)：452.2(M+H
+)。
Embodiment 6
2.45g ammonium acetate (31mmol) is dissolved in the 25ml ethanol, add 1.0g compound 1 (3.1mmol), then add 0.83g 2-trifluoromethylated benzaldehyde (4.8mmol), stirring at room 14 hours, concentrate, add 30ml water and 30ml methylene dichloride and in separating funnel, shake layering, remove organic phase, with water alkalize to the pH value for 8-9, use methylene dichloride (3 * 30) extraction then, merge organic phase, merge organic interdependent water, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, the evaporating column chromatography gets the 1.05g product, productive rate 71%.
1H?NMR(CDCl
3，300MHz)：9.15(1H，Brs.)，7.96(1H，d，J＝7.5)，7.68(1H，d，J＝7.5)，7.53(1H，t，J＝7.5)，7.40(1H，t，J＝7.5)，6.63(2H，2d，J＝8.1)，6.06(1H，brs.)，4.74(1H，d，J＝15.6)，3.78(3H，s)，2.98(3H，m)，2.55(4H，m)，2.47(3H，s)，2.39(1H，m)，2.21(1H，dt，J＝3.0，12.0)，1.97(1H，m)，1.92(1H，dt，J＝4.5，12.0)。
IR(KBr)：3512，2844，1606，1580，1482，1493，1315，1280，1126，1054，755cm
-1。
MS(ESI，m/z)：470.3(M+H
+)。
Embodiment 7
2.45g ammonium acetate (31mmol) is dissolved in 25ml acetonitrile or the ethanol, add 1.0g compound 1 (3.1mmol), then add 0.61g n-octaldehyde (4.8mmol), stirring at room 15 hours, concentrate, add 30ml water and 30ml methylene dichloride and in separating funnel, shake layering, remove organic phase, with water alkalize to the pH value for 8-9, use methylene dichloride (3 * 30) extraction then, merge organic phase, merge organic interdependent water, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, the evaporating column chromatography gets the 1.07g product, productive rate 80%.
1H?NMR(CDCl
3，300MHz)：6.62(2H，2d，J＝8.7)，4.70(1H，d，J＝15.6)，3.79(3H，s)，3.08(1H，m)，2.97(2H，m)，2.66(2H，t，J＝7.5)，2.57(2H，m)，2.44(3H，s)，2.37(3H，m)，2.17(1H，dt，J＝3.0，11.7)，1.95(1H，m)，1.85(1H，dt，J＝4.5，12.9)，1.64(2H，m)，1.22(8H，m)，0.83(3H，m)。
IR(KBr)：3517，2926，2852，1670，1482，1438，1280，1226，1064，1054，856，755cm
-1。
MS(ESI，m/z)：424.2(M+H
+)。
Embodiment 8
2.45g ammonium acetate is dissolved in the 25ml ethanol, add 1.0g compound 1 (3.1mmol), then add 0.79g 3,4-dimethoxy benzaldehyde (4.8mmol), stirring at room 20 hours, concentrate, add 30ml water and 30ml methylene dichloride and in separating funnel, shake layering, remove organic phase, with water alkalize to pH value be 8-9, use methylene dichloride (3 * 30) extraction then, merge organic phase, merge organic interdependent water, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, the evaporating column chromatography gets the 1.1g product, productive rate 85%.
1H?NMR(CDCl
3，300MHz)：7.39(1H，d，J＝1.5)，7.29(1H，dd，J＝1.5，8.4)，6.75(1H，d，J＝8.4)，6.59(2H，2d，J＝8.4)，5.88(1H，brs.)，4.71(1H，d，J＝15.9)，3.83(3H，s)，3.65(3H，s)，3.49(3H，s)，3.06(1H，m)，2.90(2H，m)，2.48(5H，m)，2.43(3H，s)，2.16(1H，dt，J＝3.0，12.0)，1.93(1H，m)，1.86(1H，dt，J＝4.5，12.6)。
IR(KBr)：3502，2908，2838，1624，1482，1438，1278，1258，1225，1024，755cm
-1。
MS(ESI，m/z)：462.2(M+H
+)。
Embodiment 9
2.45g ammonium acetate (31mmol) is dissolved in the 25ml ethanol, add 1.0g compound 1 (3.1mmol), then add 0.79g 2,4-dimethoxy benzaldehyde (4.8mmol), stirring at room 15 hours concentrates, and adds 30ml water and 30ml methylene dichloride and shake layering in separating funnel, remove organic phase, with water alkalize to the pH value for 8-9, use methylene dichloride (3 * 30) extraction then, merge organic phase, merge organic interdependent water, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, the evaporating column chromatography gets the 1.09g product, productive rate 75%.
1H?NMR(CDCl
3，300MHz)：8.16(1H，d，J＝8.4)，6.63(2H，2d，J＝8.4)，6.55(1H，dd，J＝2.4，8.4)，6.49(1H，d，J＝2.4)，4.75(1H，d，J＝15.9)，3.93(3H，s)，3.81(3H，s)，3.76(3H，s)，3.15(1H，m)，2.98(2H，m)，2.54(5H，m)，2.47(3H，s)，2.21(1H，dt，J＝3.0，12.0)，2.03(1H，m)，1.92(1H，dt，J＝4.5，12.3)。
IR(KBr)：3445，2907，2838，1615，1583，1481，1436，1280，1208，1160，1026，753cm
-1。
MS(ESI，m/z)：462.2(M+H
+)。
Embodiment 10
2.45g ammonium acetate (31mmol) is dissolved in the 25ml ethanol, add 1.0g compound 1 (3.1mmol), then add 0.64g 4-ethylbenzene formaldehyde (4.8mmol), stirring at room 20 hours, concentrate, add 30ml water and 30ml methylene dichloride and in separating funnel, shake layering, remove organic phase, with water alkalize to pH value be 8-9, use methylene dichloride (3 * 30) extraction then, merge organic phase, merge organic interdependent water, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, the evaporating column chromatography gets the 1.01g product, productive rate 74%.
1H?NMR(CDCl
3，300MHz)：
1H?NMR(CDCl
3，300MHz)：7.67(2H，d，J＝8.2)，7.10(2H，d，J＝8.2s)，，6.57(2H，2d，J＝8.3)，6.06(1H，Brs.，)，4.73(1H，d，J＝15.9)，3.73(3H，s)，3.07(1H，m)，2.95(2H，m)，2.60(2H，q，J＝7.5)，2.56(4H，m)，2.48(3H，s)，2.32(1H，m)，2.18(1H，dt，J＝3.3，12.0)，1.94(1H，m)，1.87(1H，dt，J＝4.8，12.9)，1.20(3H，t，j＝7.5)
IR(KBr)：3508，2962，2909，2841，1624，1611，1481，1438，1279，1225，1063，1053，839，754cm
-1
MS(ESI，m/z)：430.2(M+H
+)。
Embodiment 11
2.45g ammonium acetate (31mmol) is dissolved in the 25ml ethanol, add 1.0g compound 1 (3.1mmol), then add 0.64g 2 thiophene carboxaldehyde (4.8mmol), stirring at room 10 hours, concentrate, add 30ml water and 30ml methylene dichloride and in separating funnel, shake layering, remove organic phase, with water alkalize to pH value be 8-9, use methylene dichloride (3 * 30) extraction then, merge organic phase, merge organic interdependent water, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, the evaporating column chromatography gets the 1.09g product, productive rate 78%.
1H?NMR(CDCl
3，300MHz)：7.25(1H，m)，7.13(1H，dd，J＝0.9，5.1)，6.92(1H，J＝3.6，5.1)，6.60(2H，2d，J＝8.1)，6.04(1H，brs.)，4.72(1H，d，J＝15.9)，3.75(3H，s)，3.09(1H，m)，2.92(2H，m)，2.75(2H，m)，2.45(3H，s)，2.40(3H，m)，2.20(1H，dt，J＝3.6，12.0)，1.95(1H，m)，1.89(1H，dt，J＝4.5，12.9)。
IR(KBr)：3503，2908，2841，1618，1481，1437，1279，1225，1063，1053，850，754，701cm
-1。
MS(ESI，m/z)：408.2(M+H
+)。
Embodiment 12
2.45g ammonium acetate (31mmol) is dissolved in the 25ml ethanol, add 1.0g compound 1 (3.1mmol), then add 0.89g 3,5-dimethoxy 4-hydroxy benzaldehyde (4.8mmol), stirring at room 15 hours, concentrate, add 30ml water and 30ml methylene dichloride and in separating funnel, shake layering, remove organic phase, with water alkalize to pH value be 8-9, use methylene dichloride (3 * 30) extraction then, merge organic phase, merge organic interdependent water, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, the evaporating column chromatography gets the 1.09g product, productive rate 72%.
1H?NMR(CDCl
3∶CD
3OD＝10∶1，300MHz)：7.38(2H，s)，6.63(2H，2d，J＝8.4)，4.79(1H，d，J＝15.6)，3.87(6H，s)，3.78(3H，s)，3.18(1H，m)，3.02(2H，m)，2.49(3H，s)，2.46(5H，m)，2.27(1H，dt，J＝3.0，12.3)，2.03(1H，m)，1.91(1H，dt，J＝4.5，12.3)。
IR(KBr)：3503，2912，2840，1608，1482，1465，1438，1280，1224，1116，1053，754cm
-1。
MS(ESI，m/z)：478.3(M+H
+)。
Embodiment 13
2.45g ammonium acetate (31mmol) is dissolved in the 25ml ethanol, add 1.0g compound 1 (3.1mmol), then add 0.72g 4-nitrobenzaldehyde (4.8mmol), stirring at room 20 hours, concentrate, add 30ml water and 30ml methylene dichloride and in separating funnel, shake layering, remove organic phase, with water alkalize to the pH value for 8-9, use methylene dichloride (3 * 30) extraction then, merge organic phase, merge organic interdependent water, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, the evaporating column chromatography gets the 1.15g product, productive rate 82%.
1H?NMR(CDCl
3∶CD
3OD＝10∶1)：8.59(1H，t，J＝2.1)，8.13(1H，m)，8.05(1H，m)，7.15(1H，t，J＝8.4)，6.64(2H，2d，J＝8.1)，4.84(1H，d，J＝15.9)，3.78(3H，s)，3.17(1H，m)，3.03(2H，m)，2.55(5H，m)，2.48(3H，s)，2.26(1H，dt，J＝3.0，12.0)，2.07(1H，m)，1.89(1H，dt，J＝4.5，12.9)。
IR(KBr)：3609，2908，2841，1610，1539，1481，1438，1349，1278，1226，1063，1053，809，704cm
-1。
MS(ESI，m/z)：447.2(M+H
+)。
Embodiment 14
2.45g ammonium acetate (31mmol) is dissolved in the 25ml ethanol, add 1.0g compound 1 (3.1mmol), then add 0.46g furfural (4.8mmol), stirring at room 10 hours, concentrate, add 30ml water and 30ml methylene dichloride and in separating funnel, shake layering, remove organic phase, with water alkalize to the pH value for 8-9, use methylene dichloride (3 * 30) extraction then, merge organic phase, merge organic interdependent water, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, the evaporating column chromatography gets the 1.06g product, productive rate 85%.
1H?NMR(CDCl
3，300MHz)：7.31(1H，d，J＝1.8)，6.71(1H，d，J＝3.0)，6.59(2H，2d，J＝8.1)，6.39(1H，dd，J＝1.8，3.0)，6.06(1H，brs.)，4.72(1H，d，J＝15.9)，3.75(3H，s)，3.12(1H，m)，2.99(2H，m)，2.48(5H，m)，2.45(3H，s)，2.18(1H，dt，J＝3.3，12.6)，1.97(1H，m)，1.84(1H，dt，J＝4.5，12.6)。
IR(KBr)：3503，2909，2841，1604，1481，1438，1279，1224，1063，1053，1013，753cm
-1。
MS(ESI，m/z)：392.3(M+H
+)。
Embodiment 15
2.45g ammonium acetate (31mmol) is dissolved in 25ml chloroform or the ethanol, adds 1.0g compound 1 (3.1mmol), then adds 0.5.1g 3-pyridylaldehyde (4.8mmol), stirring at room 10 hours, and directly the evaporating column chromatography gets the 1.1g product, productive rate 86%.
1H?NMR(CDCl
3，300MHz)：9.23(1H，s)，8.45(1H，d，J＝3.3)，8.35(1H，d，J＝7.8)，7.31(1H，m)，6.65(1H，d，J＝6.9)，6.55(1H，d，J＝6.9)，5.19(1H，J＝16.5)，3.73(3H，s)，3.52(1H，m)，3.27(1H，m)，2.96(2H，d，J＝18.3)，2.59(8H，m)，2.185(3H，m)ppm。
MS(ESI，m/z)：403.2(M+H
+)。
Embodiment 16
2.45g ammonium acetate (31mmol) is dissolved in 25ml chloroform or the ethanol, add 1.0g compound 1 (3.1mmol), then add 0.7ml 40% acetaldehyde solution (6.2mmol), stirring at room 9 hours, concentrate, add 30ml water and 30ml methylene dichloride and in separating funnel, shake layering, remove organic phase, with water alkalize to the pH value for 8-9, use methylene dichloride (3 * 30) extraction then, merge organic phase, merge organic interdependent water, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, the evaporating column chromatography gets the 0.72g product, productive rate 67%.
1H?NMR(CDCl
3，300MHz)：6.65(2H，m)，4.68(1H，d，J＝15.6)，3.77(3H，s)，2.97(3H，m)，2.36(5H，m)，2.43(3H，s)，2.28(3H，m)，2.16(1H，dt，J＝2.7，12.6)，1.97(1H，m)，1.84(1H，dt，J＝4.2，12.6)ppm。
MS(ESI，m/z)：340.2(M+H
+)。
Embodiment 17
2.45g ammonium acetate (31mmol) is dissolved in 25ml chloroform or the ethanol, add 1.0g compound 1 (3.1mmol), then add 0.75g 2-quinoline aldehyde (4.8mmol), stirring at room 10 hours, concentrate, add 30ml water and 30ml methylene dichloride and in separating funnel, shake layering, remove organic phase, with water alkalize to the pH value for 8-9, use methylene dichloride (3 * 30) extraction then, merge organic phase, merge organic interdependent water, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, the evaporating column chromatography gets the 0.99g product, productive rate 68%.
1H?NMR(CDCl
3，300MHz)：10.65(1H，brs.)，8.14(2H，m)，7.95(1H，m)，7.77(1H，dt，J＝0.9，8.1)，7.64(1H，m)，7.46(1H，m)，6.59(2H，s)，5.96(1H，brs.)，4.67(1H，d，J＝15.9)，3.73(3H，s)，2.44(8H，m)，2.21(1H，dt，J＝3.3，12.3)，2.02(1H，m)ppm。
MS(ESI，m/z)：453.3(M+H
+)。
Embodiment 18
2.45g ammonium acetate (31mmol) is dissolved in 25ml chloroform or the ethanol, add 1.0g compound 1 (3.1mmol), then add 0.41g isovaleric aldehyde (4.8mmol), stirring at room 12 hours, concentrate, add 30ml water and 30ml methylene dichloride and in separating funnel, shake layering, remove organic phase, with water alkalize to the pH value for 8-9, use methylene dichloride (3 * 30) extraction then, merge organic phase, merge organic interdependent water, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, the evaporating column chromatography gets the 1.12g product, productive rate 76%.
1H?NMR(CDCl
3，300MHz)：6.62(2H，m)，4.67(1H，d，J＝15.9)，3.79(3H，s)，2.37(3H，m)，2.44(9H，m)，2.26(1H，m)，2.26(1H，dt，J＝3.0，12.3)，1.96(3H，m)，0.86(6H，m)ppm。
MS(ESI，m/z)：382.3(M+H
+)。
Embodiment 19
0.21g 2, the molten 0.7ml 0.025N of 5-dimethoxy-tetrahydrofuran HCl is directly used in the next step in 0 ℃ of reaction 16 hours.
2.45g ammonium acetate (31mmol) is dissolved in 25ml chloroform or the ethanol, add 1.0g compound 1 (3.1mmol), then slowly drip and go up the step reaction system, stirring at room 10 hours, concentrate, add 30ml water and 30ml methylene dichloride and in separating funnel, shake layering, remove organic phase, with water alkalize to pH value be 8-9, use the 0ml dichloromethane extraction then, remove organic phase, and the mixed extractant solvent of water usefulness methylene dichloride and methyl alcohol (10: 1) (3 * 30ml), merge organic phase, use the saturated common salt water washing, anhydrous sodium sulfate drying gets the 0.62g product, productive rate 58%.
1H?NMR(CDCl
3∶CD
3OD＝10∶1)：6.63(4H，m)，4.71(2H，d，J＝15.0)，3.80(6H，s)，2.77(10H，m)，2.23(24H，m)ppm。
MS(ESI，m/z)：677.4(M+H
+)。
Embodiment 20
0.5g compound 1 (1.59mmol) and 0.24g thiocarbamide (3.18mmol) are dissolved in the 20ml ethanol, drip the 0.05ml trifluoracetic acid, reflux 15 hours is chilled to room temperature, concentrates, add the 20ml saturated solution of sodium bicarbonate, (3 * 20ml) extractions merge organic phase and water, saturated nacl aqueous solution are washed anhydrous sodium sulfate drying successively with methylene dichloride, concentrate the 0.4g product, productive rate 71%.
1H?NMR(CDCl
3)：13.03(1H，s)，6.72(2H，s)，5.28(1H，s)，4.39(1H，brs.)，3.77(3H，s)，3.09(2H，m)，2.75(3H，m)，2.49(3H，s)，2.44(1H，m)，2.05(3H，m)。
IR(KBr)：3065，2929，2838，1606，1500，1440，1278，1255，1200，1147，1060，1030，894，749cm
-1。
MS(ESI，m/z)：356.2(M+H
+)。
Embodiment 21
0.5g compound 1 (1.59mmol) and 0.33g 1,3-dimethyl thiourea (3.18mmol) is dissolved in the 20ml ethanol, drips the 0.05ml trifluoracetic acid, reflux 11 hours, be chilled to room temperature, concentrate, add the 20ml saturated solution of sodium bicarbonate, with methylene dichloride (3 * 20ml) extractions, also water, saturated nacl aqueous solution are washed successively to merge organic phase, anhydrous sodium sulfate drying, concentrate successively analyse the 0.48g product, productive rate 79%.
1H?NMR(CDCl
3)：6.71(1H，d，J＝8.4)，6.66(2H，s)，5.41(1H，s)，3.82(3H，s)，3.72(3H，s)，3.42(3H，s)，3.27(1H，dd，J＝3.0，6.0)，3.10(1H，m)，2.56(4H，m)，2.48(3H，s)，2.38(1H，dt，J＝3.9，12.6)，1.96(3H，m)。
IR(KBr)：2928，2910，2835，1605，1504，1450，1440，1359，1275，1172，1054，1030，893，877，853，796cm
-1。
MS(ESI，m/z)：384.2(M+H
+)。
Claims (6)
1, a kind of Sinomenine derivate of C cycle connected to penetabasic heterocycle, its structural formula is as follows:
R wherein
1Be OH, R
2Be H, or R
1And R
2Common formation
R
3And R
4Be respectively C
1-14Alkyl or unsaturated hydrocarbons; R
5Be H, O, S, C
1～10Alkyl,
Have one～three substituting group or be not with substituent five yuan or hexavalent aromatic ring, nitrogen heterocyclic ring, oxygen heterocyclic ring or sulfur heterocyclic ring, described substituting group is halogen, C
1～4Alkyl or contain fluoroalkyl, nitro, itrile group, methoxyl group or hydroxyl, two keys of → representative or singly-bound.
2, a kind of Sinomenine derivate of C cycle connected to penetabasic heterocycle is characterized in that having following structural formula:
3, a kind of Sinomenine derivate of C cycle connected to penetabasic heterocycle is characterized in that having following structural formula:
4, a kind of Sinomenine derivate synthetic method of C cycle connected to penetabasic heterocycle, it is characterized in that in organic solvent and room temperature～reflux temperature under, adopt the method for (1) or (2) to make:
(1). the hydrolysate of tuduranine, aldehyde and ammonium acetate reacted 1～20 hour; The hydrolysate of described tuduranine, aldehyde and ammonium acetate mol ratio are 1: 1～2: 1～20;
(2). the hydrolysate of tuduranine, urea or thiocarbamide and organic acid or inorganic acid reaction, the time is 5-20 hour, the mol ratio of the hydrolysate of described tuduranine, urea or thiocarbamide and organic acid or mineral acid is 1: 2～3: 3～5;
The hydrolysate structural formula of described tuduranine is as follows:
The structural formula of described urea or thiocarbamide is as follows:
Described aldehyde molecular formula is R
6CHO, wherein R
1, R
2, R
3And R
4According to claim 1, R
6As described in claim 2.
5, the Sinomenine derivate synthetic method of a kind of C cycle connected to penetabasic heterocycle as claimed in claim 4, it is characterized in that described organic solvent is methyl alcohol, ethanol, Virahol, the trimethyl carbinol, methylene dichloride, chloroform, 1,2-ethylene dichloride, tetracol phenixin, ether, tetrahydrofuran (THF), benzene,toluene,xylene, acetone, butanone, acetonitrile, N, dinethylformamide or methyl-sulphoxide.
6, the Sinomenine derivate synthetic method of a kind of C cycle connected to penetabasic heterocycle as claimed in claim 4 is characterized in that described organic acid is formic acid, acetate, trifluoracetic acid or oxalic acid; Described mineral acid is hydrochloric acid or sulfuric acid.
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|---|---|---|---|---|
| CN1213372A (en) * | 1996-01-10 | 1999-04-07 | 史密丝克莱恩比彻姆股份公司 | Heterocycle-condensed morphinoid derivatives (II) |
| WO1999042105A1 (en) * | 1998-02-20 | 1999-08-26 | Avmax, Inc. | Epimorphian compound and its use |
| WO2001012196A1 (en) * | 1999-08-13 | 2001-02-22 | Southern Research Institute | Pyridomorphinans and use thereof |
| WO2004048340A1 (en) * | 2002-11-28 | 2004-06-10 | Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences | Sinomenine and sinomenine compounds, synthesis and use |
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| CN1213372A (en) * | 1996-01-10 | 1999-04-07 | 史密丝克莱恩比彻姆股份公司 | Heterocycle-condensed morphinoid derivatives (II) |
| WO1999042105A1 (en) * | 1998-02-20 | 1999-08-26 | Avmax, Inc. | Epimorphian compound and its use |
| US6372756B1 (en) * | 1998-02-20 | 2002-04-16 | Avmax, Inc. | Epimorphian compound and its use |
| WO2001012196A1 (en) * | 1999-08-13 | 2001-02-22 | Southern Research Institute | Pyridomorphinans and use thereof |
| WO2004048340A1 (en) * | 2002-11-28 | 2004-06-10 | Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences | Sinomenine and sinomenine compounds, synthesis and use |
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