CN101863908A - Oxacyclo-sulfamide spirocyclic medicament template and synthesis method thereof - Google Patents
Oxacyclo-sulfamide spirocyclic medicament template and synthesis method thereof Download PDFInfo
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Abstract
The invention discloses an oxacyclo-sulfamide spirocyclic medicament template and a synthesis method thereof. The method comprises the following steps of: first cyaniding and aminating a tetrahydro-4H-pyran-4-one or tetrahydrofuran ketone compound in a one-pot boiling manner; then reducing a cyanogroup into an amino-group; next directly performing ring closing with amino sulfamide to obtain a 2-N substituted oxacyclo-sulfamide spirocyclic medicament template (a target compound I); and finally easily obtaining a 2,5-N disubstituted oxacyclo-sulfamide spirocyclic medicament template (a target compound II), wherein the compound I and the compound II have the structural formulae. The synthesis method of the invention has the advantages of high efficiency and the large-scale preparation of the oxacyclo-sulfamide spirocyclic medicament templates.
Description
Technical field: the synthetic method that the present invention relates to a kind of Oxacyclo-sulfamide spirocyclic class 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 Oxacyclo-sulfamide spirocyclic structure 1 owing to comprise hydrogen bond receptor simultaneously and give body, and 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.
Because this compounds particular structure does not still have any document at present and patent has any report to this compounds, we think that this compounds may have good biological activity and huge medical prospect.
Recently, Merck﹠amp; Co.Inc. (US6172076) reported that the derivative that contains 2 core textures is the inhibitor of oncogene Ras proteolytic enzyme, thereby plays the effect of treatment cancer.Patent WO2003/93252, WO2003/93253, WO2003/93264, WO2004/39800, WO2005/14553, WO2005/30731 and WO2006/123185 follow-up story another kind of spirocyclic compound 3 core textures reach anticancer effect by suppressing the proteic expression of Notch, and the preparation of this type of spirocyclic compound, biological activity and huge medical prospect.
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:
Still do not have bibliographical information about the synthetic of Oxacyclo-sulfamide spirocyclic class drug template, but the main method of the synthetic bibliographical information of nitrogen heterocyclic or carbocyclic ring sulfamide spiro compounds comprises:
Document (Synlett., 2006,6,833) report is by the sulfamide spiro compound 4 of 5 replacements of 7 preparations, as shown in Equation 1:
Formula 1
Method: (i) dimethyl methyl acid amides, titanium tetraethoxide, tetrahydrofuran (THF) refluxes; (ii) Trimethylsulfoxonium Iodide, sodium hydrogen, N, N '-dimethyl sulfoxide (DMSO); (iii) Tri N-Propyl Amine, N, N '-dimethyl sulfoxide (DMSO), 100 ℃.
Document (Bioorg.Med.Chem.Lett., 2005,15,4212) reported by 8 preparation 2-hydrogen-5-hydrogen sulfamide spiro compounds, and obtained being mainly the sulfamide spiro compound 5 of 5 replacements by alkylation, a spot of 2,5 bisubstituted compounds 9 are arranged simultaneously, as shown in Equation 2:
Formula 2
Method: (i) sodium cyanide, azanol, ammonia, ammonium chloride, methyl alcohol, 0 ℃; (ii) tetrahydrochysene lithium aluminium, tetrahydrofuran (THF), room temperature; (iii) SULFAMIDE, pyridine refluxes; (iv) sodium hydrogen, bromo propane, N, N '-dimethyl formamide, room temperature.
Find that in the process of 2-hydrogen-5-hydrogen sulfamide spiro compound being carried out the alkyl derivatize because 5 NH activity are higher, alkylation in most cases obtains 5 substitution compounds in the alkylation process; But, obtain 2,5 disubstituted sulfonamide compoundss simultaneously because selectivity is relatively poor.As seen can not directly obtain the sulfonamides spirocyclic compound of 2 replacements by above literature method.
In order to obtain the sulfamide compound of 2 replacements; document (Synlett.2006; 6; 833) reported with 10 to be that raw material at first prepares the compound 11 of 5 N to the methoxybenzyl protection; then 2 N are carried out alkylation; obtain the compound 12 of 2 replacements at last indirectly by deprotection to methoxybenzyl, as shown in Equation 3:
Formula 3
Method: (i) diisopropyl azodiformate, triphenyl phosphorus, toluene refluxes; (ii) N, N '-dimethyl methyl acyl chlorides, triethylamine, methylene dichloride, room temperature; (iii) 4-Methoxybenzylamine, N, N '-dimethyl sulfoxide (DMSO), 100 degree; (iv) bromo propane, sodium hydrogen, tetrahydrofuran (THF); (v) trifluoroacetic acid.
Patent (US6172076) report, 1-benzyl-4-piperidone 13 then by hydrogenating reduction, close the sulfonamides spirocyclic compound 6 that ring directly obtains 2 replacements by SULPHURYL CHLORIDE, as shown in Equation 4 through amino and cyano groupization at last; This is the method for only so far direct Synthetic 2 position substituted sulphonamide spirocyclic compound.But this method is used expensive rhodium/alchlor catalyzer, and last pass ring step uses highly acid SULPHURYL CHLORIDE, is unfavorable for the in enormous quantities synthetic of this compounds.
Formula 4
Method: monomethylaniline (i), trimethyl silicane nitrile, Glacial acetic acid, room temperature; (ii) hydrogen (55psi), 5% rhodium/alchlor catalyzer, ethanol, room temperature; (iii) SULPHURYL CHLORIDE, methylene dichloride, room temperature.
In sum; the method of the sulfamide spiro compound that bibliographical information Synthetic 2 position replaces; promptly 2-hydrogen-5-hydrogen-oxygen heterocycle bisamide spirocyclic compound is carried out in the process of alkyl derivatize; protect 5 N earlier; then 2 N are carried out the alkyl derivatize, obtain 2 N by 5 N deprotections more at last and go up the bisamide volution compound that replaces.This method is comparatively loaded down with trivial details, and has optionally problem, does not possess the feasibility of the oxa-ring bisamide volution compound of 2 replacements of mass preparation.In our research, we improve and optimizate patent (US6172076) reported method and are applied to from oxa-cyclic ketones compounds---mainly being tetrahydrofuran (THF) ketone (n=0) class and tetrahydro pyrone (n=1) compounds---prepares the Oxacyclo-sulfamide compounds, and reaction effect is good; Reactions steps is few, only is the reaction of 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.
Summary of the invention:
The purpose of this invention is to provide a kind of Oxacyclo-sulfamide spirocyclic medicament template and synthetic method efficient, that possess mass preparation.The technical issues that need to address are: the sulfamide compound of Synthetic 2 position replacement in the past needs 5 N of protection earlier, then 2 N is carried out the alkyl derivatize, obtains the Oxacyclo-sulfamide spirocyclic compounds that 2 N upward replace by 5 N deprotections more at last.Former method reactions steps is many, and efficient is low, is unfavorable for extensive synthetic.
In the technical solution of the present invention: the Oxacyclo-sulfamide spirocyclic class drug template that fits to, its chemical structural formula is as follows:
The chemical compounds I compound ii
Wherein, n=0 or 1; R
1Be 2 substituting groups on the N, R
2Be 5 substituting groups on the N, comprise aliphatics, aromatic series and heterocyclic group, as methyl, ethyl, n-propyl, sec.-propyl, cyclopropyl, phenyl, benzyl, α position furfuryl etc.; R herein
1With R
2Can be the same or different.
Oxacyclo-sulfamide spirocyclic class drug template shown in more related above chemical compounds Is, the II in the embodiment of the invention, including, but not limited to: 14,15,16 etc.
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 tetrahydro pyrone or tetrahydrofuran (THF) ketone compounds A and primary amine B soluble in water, add sodium cyanide, reaction obtains tetrahydrofuran (THF)-3-nitrile (n=0) class or 4 tetrahydropyrans-4-nitrile (n=1) compounds C that amine replaces that 3 amine replace; Second method is a solventless method, tetrahydro pyrone or tetrahydrofuran (THF) ketone compounds A are mixed with primary amine B (non-hydrochloride), direct heating is to the certain temperature reaction, continue several minutes, drip the trimethyl silicane nitrile, be warming up to certain temperature again and continue several minutes, aftertreatment obtains tetrahydrofuran (THF)-3-nitrile (n=0) class or 4 tetrahydropyrans-4-nitrile (n=1) compounds C that amine replaces that 3 amine replace;
In the reduction reaction (C is to D), C is dissolved in anhydrous diethyl ether, adds tetrahydrochysene lithium aluminium, reacts aftertreatment in 2～4 hours and obtains reduzate, be i.e. 3 tetrahydrofuran (THF)-3-methylamine (n=0) class or 4 tetrahydropyrans-4-methylamine (n=1) compounds D that amine replaces that amine replaces;
In the ring closure reaction (D is to E), D is dissolved in pyridine, and it is added drop-wise in the pyridine solution of SULFAMIDE, after reaction finished, aftertreatment obtained the Oxacyclo-sulfamide spirocyclic compounds, and promptly 1 N goes up the spiral shell [(1 that replaces, 2, the 5-thiadiazoles)-3,3 '-tetrahydrofuran (THF)]-2,2-dioxide (n=0) class or spiral shell [(1,2, the 5-thiadiazoles)-3,4 '-tetrahydropyrans]-2,2-dioxide (n=1) compounds E;
Alkylated reaction (E is to F) can obtain the spiral shell [(1,2 of 1,3 replacement by the alkyl derivatize, the 5-thiadiazoles)-3,3 '-tetrahydrofuran (THF)]-2,2-dioxide (n=0) class or spiral shell [(1,2, the 5-thiadiazoles)-3,4 '-tetrahydropyrans]-2,2-dioxide (n=1) compounds F.
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 reduction reaction, the reductive agent that uses is tetrahydrochysene lithium aluminium, and its consumption is 1～4 times of equivalent of C, is preferably 2 times of equivalents; Range of reaction temperature 0～25 degree, preferred temperature are 15 degree; 1～4 hour reaction times; In the ring closure reaction process, the pyridine solution of D is added drop-wise in the pyridine solution of SULFAMIDE, keeps the pyridine solution of SULFAMIDE to reflux during dropping, and temperature of reaction keeps refluxing, and the reaction times spends the night; The consumption of SULFAMIDE is 1～3 times of equivalent of D, is preferably 2 times of equivalents; In alkylation process, use salt of wormwood, sodium hydrogen etc. as alkali, acetonitrile, acetone etc. be a solvent, range of reaction temperature is that room temperature to 100 is spent, reaction time range be 1 hour to spending the night.
The invention has the beneficial effects as follows: the present invention relates to a kind of Oxacyclo-sulfamide spirocyclic class drug template and synthetic method thereof, provide a kind of reactions steps few, mild condition, directly prepare the spiral shell [(1,2 of 2 replacements, the 5-thiadiazoles)-3,3 '-tetrahydrofuran (THF)]-2,2-dioxide (n=0) class or spiral shell [(1,2, the 5-thiadiazoles)-3,4 '-tetrahydropyrans]-2,2-dioxide (n=1) compounds 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 oxygen heterocyclic sulfonamide spiro 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 3～4 steps; Mild condition is avoided using expensive and dangerous reagent, and technology is simple, is easy to synthetic a large amount of Oxacyclo-sulfamide spirocyclic analog derivatives.
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
1.4-(propylamine)-tetrahydropyrans-4-nitrile is synthetic
With the 4-tetrahydro pyrone (4g, 40mmol) and propylamin hydrochloride (3.1g, 32.6mmol) in water-soluble (60mL), stirring at room 60 minutes; (1.62g 33.1mmol), continues at room temperature to stir 15 hours to add sodium cyanide then.Reaction system extracts with methylene dichloride (120mL), and (3 * 100mL), organic phase is with Na in the saturated common salt water washing
2SO
4Drying is removed solvent and is obtained the thick product 5.6g of 4-(propylamine)-tetrahydropyrans-4-nitrile, MS (m/z): 169 (M+1); Need not purifying, directly apply to next step.
2.4-Propylamino-4-amine methyl-tetrahydropyrans is synthetic
With the 1st the step in obtain the thick product 5.6g of 4-(propylamine)-tetrahydropyrans-4-nitrile (purity 45% 15mmol) is dissolved in the 150mL anhydrous diethyl ether, ice bath be cooled to 5 the degree below, add tetrahydrochysene lithium aluminium (0.95g in batches, 25mmol), back recovery temperature to 10～15 degree that finish that feed intake reacted 2 hours; Add the sodium hydroxide solution cancellation reaction of 2mL water and 2mL 10% successively, filter, filtrate obtains the thick product 3.75g of 4-Propylamino-4-amine methyl-tetrahydropyrans, MS (m/z) after being spin-dried for solvent: 173 (M+1); Need not purifying, directly apply to next step.
3.2-propyl group-spiral shell [(1,2, the 5-thiadiazoles)-4,4 '-tetrahydropyrans]-1,1-dioxide synthetic
(0.7g 7.4mmol) is dissolved in the 50mL pyridine, and heating refluxes it, slowly drips the thick product 1.52g of 4-Propylamino-4-amine methyl-tetrahydropyrans (purity 42%, pyridine 3.7mmol) (50mL) solution that obtain in the 2nd step with SULFAMIDE; After dropwising, continue to reflux and spend the night; Reaction system is returned to room temperature, add the 100mL ethyl acetate, filter, obtain thick product 2.0g after filtrate is spin-dried for; Post separates and to obtain target product 2-propyl group-spiral shell [(1,2, the 5-thiadiazoles)-4,4 '-tetrahydropyrans]-1,1-dioxide (0.25g, overall yield 29%).
1H-NMR(400MHz，CDCl
3)：δ0.90(t，J＝7.2Hz，3H)，1.48-1.58(m，6H)，1.80(m，2H)，2.82(s，2H)，3.54-3.68(m，4H)；MS(m/z)：235(M+1)。
4.2-propyl group-5-benzyl-spiral shell [(1,2, the 5-thiadiazoles)-4,4 '-tetrahydropyrans]-1, the synthetic 2-propyl group-spiral shell [(1,2 that the 3rd step was obtained of 1-dioxide, the 5-thiadiazoles)-4,4 '-tetrahydropyrans]-1,1-dioxide (0.25g, 0.001mol) and benzyl bromine (0.2g, 1.2mmol) be dissolved in the 10mL tetrahydrofuran (THF), add again salt of wormwood (0.35g, 0.0025mol), reaction system is warming up to 50 ℃, 24 hours time.Remove solvent and get thick product, post separates and obtains target product 2-propyl group-5-benzyl-spiral shell [(1,2, the 5-thiadiazoles)-4,4 '-tetrahydropyrans]-1,1-dioxide (0.26g, 80%).
1H-NMR(400MHz，CDCl
3)：δ0.92(t，J＝7.2Hz，3H)，1.50-1.68(m，6H)，1.83(m，2H)，2.85(s，2H)，3.66-3.78(m，4H)，4.48(s，2H)，7.34-7.40(m，5H)；MS(m/z)：325(M+1)。
Embodiment 2
1.4-(benzylamine)-tetrahydropyrans-4-nitrile is synthetic
With tetrahydro pyrone (2.2g, 22.7mmol) and benzylamine hydrochloride (3.6g, 25.2mmol) in water-soluble (60mL), stirring at room 30 minutes; (1.35g 27.6mmol), continued stirring at room 15 hours to add sodium cyanide then.Reaction system extracts with methylene dichloride (120mL), and (3 * 100mL), organic phase is with Na in the saturated common salt water washing
2SO
4Drying is removed solvent and is got the thick product 6g of 4-(benzylamine)-tetrahydropyrans-4-nitrile, MS (m/z): 217 (M+1); Need not purifying, directly apply to next step.
2.4-(aminomethyl)-N-benzyl-tetrahydropyrans-4-amine is synthetic
With the 1st the step in obtain the thick product 6g of 4-(benzylamine)-tetrahydropyrans-4-nitrile (purity 43% 12.1mmol) is dissolved in the 200mL anhydrous diethyl ether, ice bath be cooled to 5 the degree below, add tetrahydrochysene lithium aluminium (0.91g in batches, 23.9mmol), back recovery temperature to 10～15 degree that finish that feed intake reacted 2 hours; Add the sodium hydroxide solution cancellation reaction of 2mL water and 2mL 10% successively, filter, filtrate obtains the thick product 5.8g of 4-(aminomethyl)-N-benzyl-tetrahydropyrans-4-amine, MS (m/z) after being spin-dried for solvent: 221 (M+1); Need not purifying, directly apply to next step.
3.2-benzyl-spiral shell [(1,2, the 5-thiadiazoles)-3,4 '-tetrahydropyrans]-1,1-dioxide synthetic
With SULFAMIDE (2.0g, 20.8mmol) be dissolved in the 100mL pyridine, heating refluxes it, slowly drips the thick product 5.8g of 4-(aminomethyl)-N-benzyl-tetrahydropyrans-4-amine (purity 40%, pyridine 10.6mmol) (100mL) solution that obtain in the 2nd step; After dropwising, continue to reflux and spend the night; Reaction system is returned to room temperature, add the 200mL ethyl acetate, filter, obtain thick product 9.7g after filtrate is spin-dried for; Post separates and to obtain target product 2-benzyl-spiral shell [(1,2, the 5-thiadiazoles)-3,4 '-tetrahydropyrans]-1,1-dioxide (0.8g, overall yield 26.4%).
1H-NMR(400MHz，CDCl
3)：δ1.55(m，2H)，1.80(m，2H)，2.74(s，2H)，3.60-3.70(m，4H)，4.21(s，2H)，7.21-7.27(m，5H)；MS(m/z)：283(M+1)。
4.2-benzyl-5-ethyl-spiral shell [(1,2, the 5-thiadiazoles)-3,4 '-tetrahydropyrans]-1,1-dioxide synthetic
Go on foot the 2-benzyl-spiral shell [(1 that obtains with the 3rd, 2, the 5-thiadiazoles)-3,4 '-tetrahydropyrans]-1,1-dioxide (0.37g, 1.3mmol) and salt of wormwood (0.36g, 2.6mmol) be dissolved in the 40mL acetone, drip under the room temperature iodoethane (0.22g, 1.4mmol), reaction system is warming up to backflow, continues to stir 10 hours.Filter, remove solvent and get thick product, post separates and obtains target product 2-benzyl-5-ethyl-spiral shell [(1,2, the 5-thiadiazoles)-3,4 '-tetrahydropyrans]-1,1-dioxide (0.36g, productive rate 90%).
1H-NMR(400MHz，CDCl
3)：δ1.08(t，J＝7.2Hz，3H)，1.55(m，2H)，1.80(m，2H)，2.74(s，2H)，2.84(q，J＝7.2Hz，2H)，3.60-3.70(m，4H)，4.21(s，2H)，7.21-7.27(m，5H)；MS(m/z)：310(M+1)。
Embodiment 3
1.3-(benzylamine)-tetrahydrofuran (THF)-3-nitrile is synthetic
With 3-tetrahydrofuran (THF) ketone (1.8g, 20.5mmol) and benzylamine (2.4g 22.6mmol) mixes, and direct heating to 100 ℃ reacted 2 minutes; (3g, 30.7mmol), 100 ℃ of holding temperatures were reacted 2 minutes to add the trimethyl silicane nitrile to reaction system then.Add the 150mL methylene dichloride toward reaction system, (3 * 100mL), anhydrous sodium sulfate drying is removed solvent and is got the thick product 3.3g of 3-(benzylamine)-tetrahydrofuran (THF)-3-nitrile, MS (m/z): 203 (M+1) with the saturated common salt water washing; Need not purifying, directly apply to next step.
2.3-benzylamine-tetrahydrofuran (THF)-3-methylamine is synthetic
Synthetic crude product with 3-(benzylamine)-tetrahydrofuran (THF)-3-nitrile of obtaining in the 1st step.3.3g (purity 56% 9mmol) is dissolved in the 150mL anhydrous diethyl ether, and ice bath is cooled to below 5 degree, add in batches tetrahydrochysene lithium aluminium (0.68g, 18mmol), back recovery temperature to 10～15 degree that finishes that feeds intake reacted 3 hours; Add the sodium hydroxide solution cancellation reaction of 2mL water and 2mL 10% successively, filter, filtrate obtains the thick product 3.1g of 3-benzylamine-tetrahydrofuran (THF)-3-methylamine, MS (m/z) after being spin-dried for solvent: 207 (M+1); Need not purifying, directly apply to next step.
3.2-benzyl-spiral shell [(1,2, the 5-thiadiazoles)-3,3 '-tetrahydrofuran (THF)]-1,1-dioxide synthetic
(1.27g 13.2mmol) is dissolved in the 70mL pyridine, and heating refluxes it, slowly drips the thick product 3.1g of 3-benzylamine-tetrahydrofuran (THF)-3-methylamine (purity 45%, pyridine 6.6mmol) (70mL) solution that obtain in the 2nd step with SULFAMIDE; After dropwising, continue to reflux and spend the night; Reaction system is returned to room temperature, add the 150mL ethyl acetate, filter, obtain thick product 5g after filtrate is spin-dried for; Post separates and to obtain target product 2-benzyl-spiral shell [(1,2, the 5-thiadiazoles)-3,3 '-tetrahydrofuran (THF)]-1,1-dioxide (0.4g, overall yield 22%).
1H-NMR(300MHz，CDCl
3)：δ1.85-2.04(m，3H)，2.74-2.90(m，2H)，2.94(s，2H)，3.33(d，J＝11.4Hz，1H)，3.37(d，J＝11.7Hz，1H)，4.52(s，2H)，7.26-7.35(m，5H)；MS(m/z)：268(M+1)。
4.2-benzyl-5-methyl-spiral shell [(1,2, the 5-thiadiazoles)-3,3 '-tetrahydrofuran (THF)]-1,1-dioxide synthetic with the 2-benzyl-spiral shell [(1,2 that obtains in the 2nd step, the 5-thiadiazoles)-3,3 '-tetrahydrofuran (THF)]-1,1-dioxide (0.4g, 1.5mmol) be dissolved among the 10mL exsiccant DMF, 0 ℃ of adding with the NaH of petroleum ether (92mg, 4mmol), stirred 30 minutes, (284mg 2mmol), at room temperature continues to stir to spend the night to add methyl iodide then; Add small amount of methanol cancellation reaction, solvent is spin-dried for, add entry (10ml) with vacuum pump, with dichloromethane extraction water (3X 20mL), the organic phase anhydrous sodium sulfate drying is after the sodium sulfate filtration, be spin-dried for solvent, residue separates (200-300 order silica gel, methylene dichloride: methyl alcohol=20: 1) obtain target product 2-benzyl-5-methyl-spiral shell [(1,2 with silicagel column, the 5-thiadiazoles)-3,3 '-tetrahydrofuran (THF)]-1,1-dioxide (0.34g, 80%).
1H-NMR(300MHz，CDCl
3)：δ1.85-2.04(m，2H)，2.55(s，3H)，2.74-2.90(m，2H)，2.94(s，2H)，3.33(d，J＝11.4Hz，1H)，3.37(d，J＝11.7Hz，1H)，4.32(d，J＝16.2Hz，1H)，4.39(d，J＝15.9Hz，1H)，7.00-7.16(m，4H)，7.26-7.35(m，5H)；MS(m/z)：282(M+1)。
Embodiment 4
1.3-(aniline)-tetrahydrofuran (THF)-3-nitrile is synthetic
With 3-tetrahydrofuran (THF) ketone (2.9g, 34.2mmol) and anilinechloride (4.8g, 37.2mmol) in water-soluble (80mL), stirring at room 30 minutes; (1.82g 37.2mmol), continued stirring at room 15 hours to add sodium cyanide then.Reaction system extracts with methylene dichloride (150mL), and (3 * 150mL), organic phase is with Na in the saturated common salt water washing
2SO
4Drying is removed solvent and is got the thick product 5.2g of 3-(aniline)-tetrahydrofuran (THF)-3-nitrile, MS (m/z): 189 (M+1); Need not purifying, directly apply to next step.
2.3-(aniline)-tetrahydrofuran (THF)-3-methylamine is synthetic
With the 1st the step in obtain the thick product 5.2g of 3-(aniline)-tetrahydrofuran (THF)-3-nitrile (purity 60% 16.7mmol) is dissolved in the 200mL anhydrous diethyl ether, ice bath be cooled to 5 the degree below, add tetrahydrochysene lithium aluminium (1.9g in batches, 50.1mmol), back recovery temperature to 10～15 degree that finish that feed intake reacted 3 hours; Add the sodium hydroxide solution cancellation reaction of 4mL water and 4mL 10% successively, filter, filtrate obtains the thick product 5.3g of 3-(aniline)-tetrahydrofuran (THF)-3-methylamine, MS (m/z) after being spin-dried for solvent: 193 (M+1); Need not purifying, directly apply to next step.
3.2-phenyl-spiral shell [(1,2, the 5-thiadiazoles)-3,3 '-tetrahydrofuran (THF)]-1,1-dioxide synthetic
(1.31g 13.6mmol) is dissolved in the 60mL pyridine, and heating refluxes it, slowly drips the thick product 1.8g of 3-(aniline)-tetrahydrofuran (THF)-3-methylamine (purity 51%, pyridine 4.6mmol) (60mL) solution that obtain in the 2nd step with SULFAMIDE; After dropwising, continue to reflux and spend the night; Reaction system is returned to room temperature, add the 150mL ethyl acetate, filter, obtain thick product after filtrate is spin-dried for; Post separates and to obtain target product 2-phenyl-spiral shell [(1,2, the 5-thiadiazoles)-3,3 '-tetrahydrofuran (THF)]-1,1-dioxide (0.3g, overall yield 25%).
1H-NMR(300MHz，CDCl
3)：δ1.80-2.10(m，3H)，2.71-2.88(m，2H)，2.96(s，2H)，3.36(d，J＝11.4Hz，1H)，3.47(d，J＝11.7Hz，1H)，7.32-7.37(m，5H)；MS(m/z)：255(M+1)。
Claims (10)
1. Oxacyclo-sulfamide spirocyclic class drug template is characterized in that its chemical structural formula is as follows:
The chemical compounds I compound ii
Wherein, n=0 or 1; R
1Be 2 substituting groups on the N, R
2Be 5 substituting groups on the N, R
1, R
2A kind of in aliphatics, aromatic series or the heterocyclic group, R
1With R
2Identical or different.
2. a kind of Oxacyclo-sulfamide spirocyclic class drug template according to claim 1 is characterized in that described R
1With R
2A kind of in methyl, ethyl, n-propyl, sec.-propyl, cyclopropyl, phenyl, benzyl or the α position furfuryl.
3. the method for a synthetic Oxacyclo-sulfamide spirocyclic class drug template as claimed in claim 1 is characterized in that synthesis step is as follows:
The hydrochloride mixing of tetrahydro pyrone or tetrahydrofuran (THF) ketone compounds A and primary amine B is soluble in water, add sodium cyanide, cyano groupization and amination obtain tetrahydrofuran (THF)-3-nitrile compounds or 4 tetrahydropyrans-4-nitrile compounds C that amine replaces;
C is dissolved in anhydrous diethyl ether, adds tetrahydrochysene lithium aluminium in reaction system, obtains tetrahydrofuran (THF)-3-methylamines or 4 tetrahydropyrans-4-methylamines D that amine replaces that 3 amine replace after the reduction;
D is dissolved in pyridine, and it is added drop-wise in the pyridine solution of SULFAMIDE, reaction is spent the night and is obtained closing spiral shell [(1,2, the 5-thiadiazoles)-3 that 1 N of ring product goes up replacement, 3 '-tetrahydrofuran (THF)]-2,2-dioxide compounds or spiral shell [(1,2, the 5-thiadiazoles)-3,4 '-tetrahydropyrans]-2,2-dioxide compounds E;
E can obtain 2,5 N by the alkyl derivatize and go up disubstituted Oxacyclo-sulfamide spirocyclic compounds F, and reaction formula is as follows:
Wherein, n=0 or 1; R
1Be 2 substituting groups on the N, R
2Be 5 substituting groups on the N, R
1, R
2A kind of in aliphatics, aromatic series or the heterocyclic group, R
1With R
2Identical or different.
4. the method for a synthetic Oxacyclo-sulfamide spirocyclic class drug template as claimed in claim 1 is characterized in that synthesis step is as follows:
Tetrahydro pyrone or tetrahydrofuran (THF) ketone compounds A are mixed with the primary amine B of non-hydrochloride, and direct heating continues several minutes to the certain temperature reaction, drips the trimethyl silicane nitrile, is warming up to certain temperature again and continues several minutes, and aftertreatment obtains C;
C is dissolved in anhydrous diethyl ether, adds tetrahydrochysene lithium aluminium in reaction system, obtains D after the reduction;
D is dissolved in pyridine, and it is added drop-wise in the pyridine solution of SULFAMIDE, and reaction is spent the night and obtained closing ring product E;
E can obtain 2,5 N by the alkyl derivatize and go up disubstituted Oxacyclo-sulfamide spirocyclic compounds F, and reaction formula is as follows:
Wherein, n=0 or 1; R
1Be 2 substituting groups on the N, R
2Be 5 substituting groups on the N, R
1, R
2A kind of in aliphatics, aromatic series or the heterocyclic group, R
1With R
2Identical or different.
5. according to the synthetic method of claim 3 or 4 described Oxacyclo-sulfamide spirocyclic class drug templates, it is characterized in that described R
1With R
2A kind of in methyl, ethyl, n-propyl, sec.-propyl, cyclopropyl, phenyl, benzyl or the α position furfuryl.
6. the synthetic method of Oxacyclo-sulfamide spirocyclic compounds according to claim 3 is characterized in that, the sodium cyanide consumption is 1～2 times of equivalent of A, the temperature of reaction room temperature, and the reaction times spends the night.
7. the synthetic method of Oxacyclo-sulfamide spirocyclic compounds according to claim 4 is characterized in that, trimethyl silicane nitrile consumption is 1～2 times of equivalent of A, 90～120 ℃ of temperature of reaction.
8. according to the synthetic method of claim 3 or 4 described Oxacyclo-sulfamide spirocyclic compounds, it is characterized in that tetrahydrochysene lithium aluminium consumption is 1～4 times of equivalent of C.
9. according to the synthetic method of claim 3 or 4 described Oxacyclo-sulfamide spirocyclic compounds, it is characterized in that the SULFAMIDE consumption is 1～3 times of equivalent of D.
10. according to the synthetic method of claim 3 or 4 described Oxacyclo-sulfamide spirocyclic compounds, it is characterized in that, in alkylation process, use salt of wormwood or sodium hydrogen as alkali, acetonitrile or acetone are solvent, and range of reaction temperature is a room temperature to 100 ℃, reaction time range be 1 hour to spending the night.
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| CN112521350A (en) * | 2020-12-22 | 2021-03-19 | 江苏广域化学有限公司 | Synthetic method of 3-methylamino tetrahydrofuran |
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| CN112521350A (en) * | 2020-12-22 | 2021-03-19 | 江苏广域化学有限公司 | Synthetic method of 3-methylamino tetrahydrofuran |
| CN112521350B (en) * | 2020-12-22 | 2023-01-03 | 江苏广域化学有限公司 | Synthetic method of 3-methylamino tetrahydrofuran |
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