CN101863838A - Method for synthesizing benzodiamine spiro-ring drug template - Google Patents
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Abstract
The invention relates to a method for synthesizing a benzodiamine spiro-ring drug template. The technological method comprises the following steps: cyaniding and aminating a 1-indanone (n=1) or 1-tetralone (n=2) compound A in a one-pot synthesis manner; then, directly closing the ring by using isocyanate chlorosulfonyl and hydrochloric acid to obtain a 3, N-substituted benzodiamine spiro-ring drug template (a target compound I); and then, easily obtaining a 1,3 N-disubstituted benzodiamine spiro-ring drug template (a target compound II) through the alkylation reaction on 1, N, wherein the structural formulas of the compound I and the compound II are shown in the accompanying drawing. The method of the invention constitutes a synthesis method for the large-scale preparation of benzodiamine spiro-ring drug templates.
Description
Technical field: the synthetic method that the present invention relates to a kind of benzodiamine spiro-ring drug template.
Background technology:
Early than the seventies in 20th century, volution compound is found biologically active.Develop through 30 years of researches, multiple volution analog derivative has been proved has the therapeutic action that has a extensive future, as antidepressant, the generation (antitumor) that suppresses new vessel, antiplatelet cohesion (antithrombotic), anti-Alzheimer thatch disease (senile dementia) etc.In the benzo bisamide spirane structure 1 owing to comprise hydrogen bond receptor simultaneously and give body (R
2=H).Hydrogen bond receptor and have the effect chance that can increase substrate and target spot when giving body, thereby may improve the conjugation of substrate and albumen target spot, reaching increases the active effect of substrate, is extensively proved to have various physiologically actives, receives a lot of concerns recently.
Merck ﹠amp; Co.Inc. (WO2008/112159A2), Pfizer Inc. (US4283409A1) has reported that the compound that contains 2 core textures has good hypoglycemic activity, thereby can be used for treating the disease relevant with blood sugar, as: diabetes, sacred disease, retinopathy etc.
Below be disclosed in partial monopoly or the document, and the example of the closely-related several compounds of the technology of the present invention:
About synthesizing of benzodiamine spiro-ring drug template, the main method of bibliographical information comprises:
Document (J.Org.Chem.2006,71,5303) report is by 1-Tetralone an intermediate of Sertraline Synthetic 2 [n=2, R
1=R
2=H], as shown in Equation 1:
Formula 1
Method: (i) potassium cyanide, volatile salt, ethanol, water
The analogue of compound 2 can prepare the benzo bisamide class volution compound of 1 or 3 replacement often as the intermediate of benzodiamine spiro-ring compound by the alkyl derivatize.The majority of reporting in the document is that 1 N goes up the compound that replaces, for example, and by (Farmaco, 1998,169) report compound 3[n=2, R
1=H, R
2=(CH
2)
4Cl] synthetic, as shown in Equation 2:
Formula 2
Method: (i) potassiumiodide, 1-bromo-4-chlorobutane, acetone
And (J.Org.Chem.2006,71,5303) report, find that selectivity is relatively poor in the alkylation process in the process of 1-hydrogen-3-hydrogen bisamide spirocyclic compound being carried out the alkyl derivatize, 1 NH activity is higher, alkylation in most cases obtains 1, the mixture of 3 bisubstituted compounds and 1 substitution compound can not directly obtain the bisamide spirocyclic compound of 3 replacements, as shown in Equation 3:
Formula 3
Method: the benzyl bromine, salt of wormwood, potassiumiodide, toluene, hexaoxacyclooctadecane-6-6 refluxes
The method of the benzo bisamide spirocyclic compound of synthetic 3 replacements of bibliographical information mainly is that 1-hydrogen-3-hydrogen benzo bisamide spirocyclic compound is carried out in the process of alkyl derivatize; protect 1 N earlier; then 3 N are carried out the alkyl derivatize, obtain the method that 3 N go up the benzodiamine spiro-ring compound that replaces by 1 N deprotection more at last.With (WO2007/61676; WO2007/61695) be reported as example explanation, n=1 wherein, R
1=Bn, R
2=H, as shown in Equation 4:
Formula 4
Method: (i) 4-methoxyl group benzylalcohol, diethylazodicarboxylate, triphenyl phosphorus, tetrahydrofuran (THF); (ii) benzyl bromine, sodium hydrogen, N, dinethylformamide; (iii) cerous ammonium nitrate (IV), acetonitrile, water;
In sum; the method of the benzo bisamide spirocyclic compound of synthetic 3 replacements of bibliographical information; promptly 1-hydrogen-3-hydrogen benzo bisamide spirocyclic compound is carried out in the process of alkyl derivatize; protect 1 N earlier; then 3 N are carried out the alkyl derivatize, obtain 3 N by 1 N deprotection more at last and go up the benzodiamine spiro-ring compound that replaces.This method is comparatively loaded down with trivial details, and has optionally problem, does not possess the feasibility of the benzo bisamide spirocyclic compound of 3 replacements of mass preparation.
Summary of the invention:
The purpose of this invention is to provide a kind of efficient, synthetic method of possessing the mass preparation benzodiamine spiro-ring drug template; the technical issues that need to address are: synthetic in the past this compounds needs 1 N of protection earlier; then 3 N are carried out the alkyl derivatize, obtain 3 N by 1 N deprotection more at last and go up the benzodiamine spiro-ring compound that replaces.Former method reactions steps is many, and efficient is low, is unfavorable for extensive synthetic.
In the technical solution of the present invention: the benzodiamine spiro-ring drug template that fits to, its chemical structural formula is as follows:
The chemical compounds I compound ii
Wherein, n=1 or 2; R
1Be 3 substituting groups on the N, R
2Be 1 substituting group on the N, comprise aliphatics, aromatic series and heterocyclic, as methyl, ethyl, n-propyl, sec.-propyl, cyclopropyl, phenyl, benzyl, α position furfuryl etc.; R herein
1With R
2Can be the same or different.
Related to the benzodiamine spiro-ring drug template shown in some above chemical compounds Is, the II in the embodiment of the invention, including, but not limited to: 8,9 etc.
The present invention will improve the synthetic method of above-mentioned drug template.Synthesis technique of the present invention specifically is summarized as follows:
In the above-mentioned technology, there are two kinds of methods in cyano group reaction (A is to the C) step: first kind, mix the hydrochloride of 1-indone (n=1) class or 1-Tetralone an intermediate of Sertraline (n=2) compounds A and primary amine B soluble in water, add sodium cyanide, reaction obtains 2 of 1 amine replacement, 3-dihydro-1H-indenes-1-nitrile (n=1) class or 1,2,3,4-tetrahydrochysene-naphthalene-1-nitrile (n=2) compounds C; Second method is a solventless method, 1-indone (n=1) class or 1-Tetralone an intermediate of Sertraline (n=2) compounds A are mixed with primary amine B (non-hydrochloride), direct heating to 90~120 ℃, question response 1~5 minute drips the trimethyl silicane nitrile, be warming up to 90~120 ℃ of reactions 1~5 minute again, aftertreatment obtains 2 of 1 amine replacement, 3-dihydro-1H-indenes-1-nitrile (n=1) class or 1,2,3,4-tetrahydrochysene-naphthalene-1-nitrile (n=2) compounds C;
In the ring closure reaction (C is to D), C is dissolved in methylene dichloride, drip the dichloromethane solution of isocyanic ester SULPHURYL CHLORIDE, reaction solution is spin-dried for and adds hydrochloric acid behind the solvent and close ring and obtain the benzodiamine spiro-ring compound, promptly 3 go up replace 2 ', 3 '-dihydro spiral shell [tetrahydroglyoxaline-4,1 '-indenes]-2,5-diketone (n=1) class or 3 ', 4 '-dihydro-2 ' H-spiral shell [tetrahydroglyoxaline-4,1 '-naphthalene]-2,5-diketone (n=2) compounds D;
Alkylated reaction (D is to E), can by the alkyl derivatize obtain 2 of 1,3 replacement ', 3 '-the dihydro spiral shell [tetrahydroglyoxaline-4,2 '-indenes]-2,5-diketone (n=1) class or 3 ', 4 '-dihydro-2 ' H-spiral shell [tetrahydroglyoxaline-4,2 '-naphthalene]-2,5-diketone (n=2) compounds E.
In above-mentioned reaction process, the cyanating reagent of employing is sodium cyanide or trimethyl silicane nitrile.When using sodium cyanide as cyanating reagent, its consumption is 1~2 times of equivalent of A, is preferably 1.2 times of equivalents, and temperature of reaction is a room temperature, and the reaction times spends the night; When using the trimethyl silicane nitrile as cyanating reagent, its consumption is 1~2 times of equivalent of A, is preferably 1.2 times of equivalents, and temperature is 90~120 ℃, is preferably 100 ℃; In the ring closure reaction process, drip the dichloromethane solution of isocyanic ester SULPHURYL CHLORIDE, isocyanic ester SULPHURYL CHLORIDE consumption is 1~4 times of equivalent of C, is preferably 2~3 times of equivalents, and the concentration of hydrochloric acid is 1mol/L, and temperature of reaction refluxes, 1~3 hour reaction times.
The invention has the beneficial effects as follows: the present invention relates to a kind of improvement of synthetic method of benzodiamine spiro-ring drug template, provide a kind of reactions steps few, mild condition, directly the preparation 3 replacements 2 ', 3 '-the dihydro spiral shell [tetrahydroglyoxaline-4,1 '-indenes]-2,5-diketone (n=1) class or 3 ', 4 '-dihydro-2 ' H-spiral shell [tetrahydroglyoxaline-4,1 '-naphthalene]-2,5-diketone (n=2) compounds is a kind of synthetic method that preparation is worth that has.This class drug template can be in conjunction with " combinatorial chemistry " technology platform, synthesize in a large number at the structurally-modified compound library of known benzodiamine spiro-ring drug template at short notice, further screening can help to obtain biological activity better medicament precursor compound.In the technology of the present invention, reactions steps is few, only is the reaction of 2~3 steps; Mild condition is avoided using expensive and dangerous reagent, and technology is simple, is easy to synthetic a large amount of this analog derivative.
Embodiment:
Following example helps to understand content of the present invention, the present invention includes but is not limited to following related content:
Embodiment 1
(1.2-propylamine)-2,3-dihydro-2H-indenes-1-nitrile synthetic
With the 1-indone (10g, 0.076mol) and propylamin hydrochloride (8g, 0.084mol) in water-soluble (120mL), stirring at room 30 minutes; (4.1g 0.084mol), continued stirring at room 15 hours to add sodium cyanide then.Reaction system extracts with methylene dichloride (200mL), the saturated common salt water washing, and organic phase is with Na
2SO
4Drying is removed solvent and is obtained 1-(propylamine)-2, the 3-dihydro-thick product 10g of 2H-indenes-1-nitrile, MS (m/z): 201 (M+1); Need not purifying, directly apply to next step.
2.3-propyl group-1 ', 3 '-dihydro spiral shell [tetrahydroglyoxaline-4,2 '-indenes]-2,5-diketone synthetic
With the 1-(propylamine)-2 that obtains in 1 step, (purity 50% 0.01mol) is dissolved in the 200mL methylene dichloride 3-dihydro-thick product 4g of 2H-indenes-1-nitrile, drips isocyanic ester SULPHURYL CHLORIDE (2.8g under the room temperature, 0.02mol) dichloromethane solution (50mL), reaction solution is restir 2 hours at room temperature; After solvent (250mL) is removed in decompression, add the hydrochloric acid 150mL of 1mol/L, be heated to and reflux and reacted 2 hours; Cooling back methylene dichloride (250mL) extractive reaction system after dried over sodium sulfate, is filtered and is removed solvent and obtain thick product; Post separate obtain target product 3-propyl group-2 ', 3 '-dihydro spiral shell [tetrahydroglyoxaline-4,1 '-indenes]-2,5-diketone (1.6g, 65%).
1H-NMR(400MHz,CDCl
3):δ0.72(t,J=7.2Hz,3H),1.34-1.44(m,2H),2.99(t,J=6.4Hz,2H),3.13(d,J=16.8Hz,2H),3.63(d,J=16.8Hz,2H),7.21-7.26(m,4H);MS(m/z):245(M+1)。
3.1-benzyl-3-propyl group-2 ', 3 '-dihydro spiral shell [tetrahydroglyoxaline-4,1 '-indenes]-2,5-diketone synthetic
The 3-propyl group-2 that 2 steps were obtained ', 3 '-dihydro spiral shell [tetrahydroglyoxaline-4,1 '-indenes]-2,5-diketone (1g, 0.004mol) and the benzyl bromine (0.84g 0.005mol) is dissolved in the 100mL acetonitrile, adds salt of wormwood (1.1g again, 0.011mol), reaction system is warming up to 70 ℃, 14 hours time.Remove solvent and get thick product, post separate obtain target product 1-benzyl-3-propyl group-2 ', 3 '-dihydro spiral shell [tetrahydroglyoxaline-4,1 '-indenes]-2,5-diketone (1.1g, 82%).
1H-NMR(400MHz,CDCl
3):δ0.67(t,J=7.6Hz,3H),1.32-1.38(m,2H),2.97(t,J=7.6Hz,2H),3.02(d,J=16.8Hz,2H),3.56(d,J=16.8Hz,2H),4.67(s,2H),7.21-7.38(m,9H);MS(m/z):335(M+1)。
Embodiment 2
(1.2-cyclopropylamine)-2,3-dihydro-2H-indenes-1-nitrile synthetic
With the 1-indone (10g, 0.076mol) and the cyclopropylamine hydrochloride (7.8g, 0.084mol) in water-soluble (120mL), stirring at room 30 minutes; (4.1g 0.084mol), continued stirring at room 15 hours to add sodium cyanide then.Reaction system extracts with methylene dichloride (200mL), the saturated common salt water washing, and organic phase is with Na
2SO
4Drying is removed solvent and is got 1-(cyclopropylamine)-2, the 3-dihydro-thick product 11g of 2H-indenes-1-nitrile, MS (m/z): 199 (M+1); Need not purifying, directly apply to next step.
2.3-cyclopropyl-2 ', 3 '-dihydro spiral shell [tetrahydroglyoxaline-4,1 '-indenes]-2,5-diketone synthetic
With the 1-(cyclopropylamine)-2 that obtains in 1 step, the thick product 3.5g (purity 45% of 3-dihydro-2H-indenes-1-nitrile, 0.008mol) be dissolved in the 150mL methylene dichloride, drip isocyanic ester SULPHURYL CHLORIDE (3.4g under the room temperature, 0.024mol) methylene dichloride (50mL) solution, reaction solution is restir 2 hours at room temperature; After solvent (200mL) is removed in decompression, add the hydrochloric acid 120mL of 1mol/L, be heated to and reflux and reacted 2 hours; Cooling back methylene dichloride (200mL) extractive reaction system after dried over sodium sulfate, is filtered and is removed solvent and obtain thick product; Post separate obtain target product 3-cyclopropyl-2 ', 3 '-dihydro spiral shell [tetrahydroglyoxaline-4,1 '-indenes]-2,5-diketone (1g, 52%).
1H-NMR(400MHz,CDCl
3):δ0.38-0.43(m,2H),0.71-0.75(m,2H),2.11-2.16(m,1H),3.21(d,J=16.8Hz,2H),3.61(d,J=16.8Hz,2H),7.22-7.26(m,4H);MS(m/z):243(M+1)。
Embodiment 3
(1.1-benzylamine)-2,3-dihydro-1H-indenes-1-nitrile synthetic
With the 1-indone (3g, 0.023mol) and benzylamine hydrochloride (3.6g, 0.025mol) in water-soluble (60mL), stirring at room 30 minutes; (1.35g 0.025mol), continued stirring at room 15 hours to add sodium cyanide then.Reaction system extracts with methylene dichloride (120mL), the saturated common salt water washing, and organic phase is with Na
2SO
4Drying is removed solvent and is got 1-(benzylamine)-2, the 3-dihydro-thick product 5g of 1H-indenes-1-nitrile, MS (m/z): 249 (M+1); Need not purifying, directly apply to next step.
2.3-benzyl-2 ', 3 '-dihydro spiral shell [tetrahydroglyoxaline-4,1 '-indenes]-2,5-diketone synthetic
With the 1-(benzylamine)-2 that obtains in 1 step, the thick product 3g (purity 55% of 3-dihydro-1H-indenes-1-nitrile, 0.007mol) be dissolved in the 150mL methylene dichloride, drip isocyanic ester SULPHURYL CHLORIDE (1.87g under the room temperature, 0.013mol) methylene dichloride (50mL) solution, reaction solution is restir 2 hours at room temperature; After solvent (200mL) is removed in decompression, add the hydrochloric acid 120mL of 1mol/L, be heated to and reflux and reacted 2 hours; Cooling back methylene dichloride (200mL) extractive reaction system after dried over sodium sulfate, is filtered and is removed solvent and obtain thick product; Post separate obtain target product 3-benzyl-2 ', 3 '-dihydro spiral shell [tetrahydroglyoxaline-4,1 '-indenes]-2,5-diketone (1.6g, 78%).
1H-NMR(400MHz,CDCl
3):δ2.97(d,J=16.8Hz,2H),3.58(d,J=16.8Hz,2H),4.31(s,2H),6.86(d,J=7.6Hz,2H),7.05-7.35(m,7H);MS(m/z):293(M+1)。
Embodiment 4
(1.1-4-chloroaniline)-2,3-dihydro-1H-indenes-1-nitrile synthetic
With the 1-indone (4g, 0.03mol) and p-Chlorobenzoic acid amide (3.86g 0.03mol) mixes, and direct heating to 95 ℃ reacted 4 minutes; (3.6g, 0.036mol), 95 ℃ of holding temperatures were reacted 4 minutes to add the trimethyl silicane nitrile to reaction system then.Add the 150mL methylene dichloride toward reaction system, use the saturated common salt water washing, anhydrous sodium sulfate drying is removed solvent and is got 1-(4-chloroaniline)-2, the 3-dihydro-thick product 6g of 1H-indenes-1-nitrile, MS (m/z): 269 (M+1); Need not purifying, directly apply to next step.
(2.3-4-chloro-phenyl-)-2 ', 3 '-dihydro spiral shell [tetrahydroglyoxaline-4,1 '-indenes]-2,5-diketone synthetic
With the 1-(4-chloroaniline)-2 that obtains in 1 step, the thick product 3.23g (purity 60% of 3-dihydro-1H-indenes-1-nitrile, 0.007mol) be dissolved in the 150mL methylene dichloride, drip isocyanic ester SULPHURYL CHLORIDE (1.87g under the room temperature, 0.013mol) methylene dichloride (50mL) solution, reaction solution is restir 2 hours at room temperature; After solvent (200mL) is removed in decompression, add the hydrochloric acid 120mL of 1mol/L, be heated to and reflux and reacted 2 hours; Cooling back methylene dichloride (200mL) extractive reaction system after dried over sodium sulfate, is filtered and is removed solvent and obtain thick product; The post separation obtains 1.3g target product 3-(4-chloro-phenyl-)-2 ', 3 '-the dihydro spiral shell [tetrahydroglyoxaline-4,1 '-indenes]-2,5-diketone (1.3g, 60%).
1H-NMR(400MHz,CDCl
3):δ3.35(d,J=16.0Hz,2H),3.69(d,J=16.0Hz,2H),7.08-7.18(m,8H);MS(m/z):311(M-1)。
Embodiment 5
(1.1-furans-2-methylamine)-2,3-dihydro-1H-indenes-1-nitrile synthetic
With the 1-indone (2g, 0.015mol) and furans-2-methylamine (1.47g 0.015mol) mixes, and direct heating to 110 ℃ reacted 3 minutes; (3g, 0.03mol), 110 ℃ of holding temperatures were reacted 3 minutes to add the trimethyl silicane nitrile to reaction system then.Add the 100mL methylene dichloride toward reaction system, use the saturated common salt water washing, anhydrous sodium sulfate drying is removed solvent and is got 1-(furans-2-methylamine)-2, the 3-dihydro-thick product 3.4g of 1H-indenes-1-nitrile, MS (m/z): 239 (M+1); Need not purifying, directly apply to next step.
(2.3-furans-2-methyl)-2 ', 3 '-dihydro spiral shell [tetrahydroglyoxaline-4,1 '-indenes]-2,5-diketone synthetic
With the 1-(furans-2-methylamine)-2 that obtains in 1 step, the thick product 3.4g (purity 60% of 3-dihydro-1H-indenes-1-nitrile, 0.008mol) be dissolved in the 150mL methylene dichloride, drip isocyanic ester SULPHURYL CHLORIDE (2.2g under the room temperature, 0.015mol) methylene dichloride (50mL) solution, reaction solution is restir 2 hours at room temperature; After solvent (200mL) is removed in decompression, add the hydrochloric acid 100mL of 1mol/L, be heated to and reflux and reacted 2 hours; Cooling back methylene dichloride (150mL) extractive reaction system after dried over sodium sulfate, is filtered and is removed solvent and obtain thick product; The post separation obtains target product 3-(furans-2-methyl)-2 ', 3 '-the dihydro spiral shell [tetrahydroglyoxaline-4,1 '-indenes]-2,5-diketone (0.9g, 40%).
1H-NMR(400MHz,CDCl
3):δ2.61(t,J=16.8Hz,2H),3.23(t,J=16.8Hz,2H),4.23(s,2H),5.63(d,J=3.2Hz,1H),6.15(t,J=2.0Hz,1H),7.10-7.30(m,5H);MS(m/z):283(M+1)。
Embodiment 6
(1.1-ethamine)-1,2,3,4-tetrahydrochysene-naphthalene-1-nitrile synthetic
With the 1-Tetralone an intermediate of Sertraline (0.6g, 0.004mol) and ethamine (0.45g 0.01mol) mixes, and direct heating to 100 ℃ reacted 2 minutes; (1.63g, 0.016mol), 100 ℃ of holding temperatures were reacted 2 minutes to add the trimethyl silicane nitrile to reaction system then.Add the 50mL methylene dichloride toward reaction system, use the saturated common salt water washing, anhydrous sodium sulfate drying is removed solvent and is got 1-(ethamine)-1,2,3, the thick product 0.85g of 4-tetrahydrochysene-naphthalene-1-nitrile, MS (m/z): 201 (M+1); Need not purifying, directly apply to next step.
2.3-ethyl-3 ', 4 '-dihydro-2 ' H-spiral shell [tetrahydroglyoxaline-4,1 '-naphthalene]-2,5-diketone synthetic
With the 1-(ethamine)-1 that obtains in the 1st step, 2,3, the thick product 0.85g (purity 53% of 4-tetrahydrochysene-naphthalene-1-nitrile, 0.0017mol) be dissolved in the 40mL methylene dichloride, (0.55g, methylene dichloride 0.004mol) (25mL) solution, reaction solution be restir 2 hours at room temperature to drip the isocyanic ester SULPHURYL CHLORIDE under the room temperature; After solvent (65mL) is removed in decompression, add the hydrochloric acid 50mL of 1mol/L, be heated to and reflux and reacted 2 hours; Cooling back methylene dichloride (70mL) extractive reaction system after dried over sodium sulfate, is filtered and is removed solvent and obtain thick product; Post separate obtain target product 3-ethyl-3 ', 4 '-dihydro-2 ' H-spiral shell [tetrahydroglyoxaline-4,1 '-naphthalene]-2,5-diketone (0.37g, 60%).
1H-NMR(400MHz,CDCl
3):δ1.10(t,J=8.2Hz,3H),1.88-1.99(m,4H),2.23(dd,J=7.3,7.Hz,1H),2.60(tet,J=8.22H),3.00-3.08(m,2H),6.93(m,2H),7.05(d,J=7.5Hz,1H),7.42(s,J=8.0Hz,1H);MS(m/z):245(M+1)。
3.3-ethyl-1-benzyl-3 ', 4 '-dihydro-2 ' H-spiral shell [tetrahydroglyoxaline-4,1 '-naphthalene]-2, the synthetic 3-ethyl-3 that the 2nd step was obtained of 5-diketone ', 4 '-dihydro-2 ' H-spiral shell [tetrahydroglyoxaline-4,1 '-naphthalene]-2,5-diketone (0.1g, 0.4mmol) and benzyl bromine (85mg, 0.5mmol) be dissolved in the 100mL acetonitrile, add again salt of wormwood (138mg, 1mmol), reaction system is warming up to 70 ℃, 14 hours time.Remove solvent and get thick product, post separate obtain target product 3-ethyl-1-benzyl-3 ', 4 '-dihydro-2 ' H-spiral shell [tetrahydroglyoxaline-4,1 '-naphthalene]-2,5-diketone (107mg, 80%).
1H-NMR(400MHz,CDCl
3):δ1.10(t,J=8.2Hz,3H),1.88-1.99(m,4H),2.60(t,J=8.2Hz,2H),3.00-3.08(m,2H),4.55(s,2H),6.93(m,2H),7.05(d,J=7.5Hz,1H),7.24-7.28(m,5H),7.42(d,J=8.0Hz,1H);MS(m/z):335(M+1)。
Claims (10)
1. the synthetic method of a benzodiamine spiro-ring drug template, it is characterized in that, synthesis step is as follows: the first step reaction mixes the hydrochloride of 1-indone (n=1) class or 1-Tetralone an intermediate of Sertraline (n=2) compounds A and primary amine B soluble in water, add sodium cyanide, cyano groupization and amination obtain Compound C; The second step reaction is that Compound C is dissolved in methylene dichloride, drips the dichloromethane solution of isocyanic ester SULPHURYL CHLORIDE, and reaction solution is spin-dried for and adds hydrochloric acid behind the solvent and close ring and obtain the benzodiamine spiro-ring Compound D; Three-step reaction is that Compound D is obtained 1,3 disubstituted benzodiamine spiro-ring compd E of N by the alkyl derivatize, and reaction formula is as follows:
Wherein, n=1 or 2; R
1Be 3 substituting groups on the N, R
2Be 1 substituting group on the N, R
1With R
2Be selected from a kind of group in aliphatics, aromatic series or the heterocyclic, R
1With R
2Identical or different.
2. the synthetic method of a benzodiamine spiro-ring drug template, it is characterized in that, synthesis step is as follows: the first step reaction mixes 1-indone (n=1) class or 1-Tetralone an intermediate of Sertraline (n=2) compounds A with the primary amine B of non-hydrochloride, the direct heating reaction, reheat reacts after dripping the trimethyl silicane nitrile, and aftertreatment obtains Compound C; The second step reaction is that Compound C is dissolved in methylene dichloride, drips the dichloromethane solution of isocyanic ester SULPHURYL CHLORIDE, and reaction solution is spin-dried for and adds hydrochloric acid behind the solvent and close ring and obtain the benzodiamine spiro-ring Compound D; Three-step reaction is that Compound D is obtained 1,3 disubstituted benzodiamine spiro-ring compd E of N by the alkyl derivatize, and reaction formula is as follows:
Wherein, n=1 or 2; R
1Be 3 substituting groups on the N, R
2Be 1 substituting group on the N, R
1With R
2Be selected from a kind of group in aliphatics, aromatic series or the heterocyclic, R
1With R
2Identical or different.
3. the synthetic method of a kind of benzodiamine spiro-ring drug template according to claim 1 and 2 is characterized in that, R
1With R
2Be selected from a kind of in methyl, ethyl, n-propyl, sec.-propyl, cyclopropyl, phenyl, benzyl or the α position furfuryl.
4. the synthetic method of a kind of benzodiamine spiro-ring drug template according to claim 1 is characterized in that, its consumption of sodium cyanide is 1~2 times of equivalent of compd A, the temperature of reaction room temperature, and the reaction times spends the night.
5. the synthetic method of a kind of benzodiamine spiro-ring drug template according to claim 4 is characterized in that, its consumption of sodium cyanide is 1.2 times of equivalents of compd A.
6. the synthetic method of a kind of benzodiamine spiro-ring drug template according to claim 2 is characterized in that, trimethyl silicane nitrile consumption is 1~2 times of equivalent of compd A, 90~120 ℃ of temperature of reaction.
7. the synthetic method of a kind of benzodiamine spiro-ring drug template according to claim 6 is characterized in that, trimethyl silicane nitrile consumption is 1.2 times of equivalents of compd A, 100 ℃ of temperature of reaction.
8. the synthetic method of a kind of benzodiamine spiro-ring drug template according to claim 1 and 2 is characterized in that, in the second step reaction process, isocyanic ester SULPHURYL CHLORIDE consumption is 1~4 times of equivalent of Compound C; Hydrochloric acid uses the hydrochloric acid of 1mol/L.
9. the synthetic method of a kind of benzodiamine spiro-ring drug template according to claim 8 is characterized in that, isocyanic ester SULPHURYL CHLORIDE consumption is 2~3 times of equivalents of Compound C.
10. the synthetic method of a kind of benzodiamine spiro-ring drug template according to claim 1 and 2 is characterized in that, in the three-step reaction process, use salt of wormwood or sodium hydrogen as alkali, acetonitrile or acetone are solvent, and temperature of reaction is a room temperature to 100 ℃, and 1 hour reaction times is to spending the night.
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