CN102070634B - Method for synthesizing 1,7-diazaspiro[4.5]decane with protective group - Google Patents
Method for synthesizing 1,7-diazaspiro[4.5]decane with protective group Download PDFInfo
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- CN102070634B CN102070634B CN200910201862XA CN200910201862A CN102070634B CN 102070634 B CN102070634 B CN 102070634B CN 200910201862X A CN200910201862X A CN 200910201862XA CN 200910201862 A CN200910201862 A CN 200910201862A CN 102070634 B CN102070634 B CN 102070634B
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- 0 *N(CCC1)CC1[N+]([O-])=O Chemical compound *N(CCC1)CC1[N+]([O-])=O 0.000 description 3
- OKTKWLDFMRBBTE-UHFFFAOYSA-N CC(C)(C)OC(N(CCC1)CC1(CC1)NC1=O)=O Chemical compound CC(C)(C)OC(N(CCC1)CC1(CC1)NC1=O)=O OKTKWLDFMRBBTE-UHFFFAOYSA-N 0.000 description 1
- BDJBFOXMOFAKJU-UHFFFAOYSA-N COC(CCC(CCC1)(CN1OC(c1ccccc1)=O)[N+]([O-])=O)=O Chemical compound COC(CCC(CCC1)(CN1OC(c1ccccc1)=O)[N+]([O-])=O)=O BDJBFOXMOFAKJU-UHFFFAOYSA-N 0.000 description 1
- IDWLWFSDRFNDEL-QBFSEMIESA-N O/N=C(/CCC1)\CN1OC(c1ccccc1)=O Chemical compound O/N=C(/CCC1)\CN1OC(c1ccccc1)=O IDWLWFSDRFNDEL-QBFSEMIESA-N 0.000 description 1
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Abstract
The invention relates to a method for preparing 1,7-diazaspiro[4.5]decane and derivatives thereof, and mainly solves the technical problems that the synthetic route is long, the yield is low, an intermediate is difficult to purify, reaction conditions are rigorous, and mass production cannot be performed in the prior art. The method comprises the following steps of: performing Michael addition reaction on N-PG-3-nitropyridine serving as a raw material and acrylic ester or acrolein in alcoholic solution or acetonitrile to obtain N-PG-3-(3-nitropyridine-3-yl)propionate or N-PG-3-propanal-3-nitropyridine; adding a catalyst into the product in an organic solvent, and performing hydrogenation reduction ring-closing reaction to obtain 1,7-diaza-2-oxy-spiro[4.5]decane with a protective group or 1,7-diazaspiro[4.5]decane with a protective group; and adding a reducing agent into the 1,7-diaza-2-oxy-spiro[4.5]decane with the protective group in the organic solvent to obtain the 1,7-diazaspiro[4.5]decane with the protective group. The method has the advantages of a few reaction steps, high yield and mild conditions, and is a synthetic method with large-scale preparation value.
Description
Technical field: the present invention relates to a kind of with 1 of protecting group, the preparation method of 7-diaza spiro [4,5] certain herbaceous plants with big flowers alkane.
Background technology:
1,7-diaza spiro [4,5] the certain herbaceous plants with big flowers alkane derivatives is a kind of useful pharmaceutical intermediate, the compound that the WO2005/097794A1 report contains this class core texture has neurokinin active, particularly has the NK1 antagonistic activity, NK1/NK2 antagonistic activity, the NK1/NK3 antagonistic activity of associating and the NK1/NK2/NK3 antagonistic activity of associating of associating.Be mainly used in treating and or prevent the medicinal application of following illness: schizophrenia, vomiting, anxiety disorder and dysthymia disorders, irritable bowel syndrome (IBS), circadian rhythm disorder, preeclampsia, nociception, pain, particularly internal organ and neuropathic pain, pancreatitis, neurogenic inflammation, asthma, chronic obstructive pulmonary disease (COPD) and the dysuria urinary incontinence etc.
For the preparation of 1,7-diaza spiro [4,5] certain herbaceous plants with big flowers alkane derivatives, bibliographical information related compound method is as follows:
Method 1 is by WO2005/097794A1 report, wherein PG
1=Bz, PG2=Bn, overall yield 10.6%, as shown in Equation 1:
Formula 1
Reagent and productive rate: (I) Benzoyl chloride, triethylamine, methylene dichloride; (II) hexamethyldisilane amine base lithium, tetrahydrofuran (THF), propylene bromine ,-78 ℃, 96%2 steps; (III) borine, tetrahydrofuran (THF), 35% hydrogen peroxide, 31%; (IV) DIAD, O-phthalic acid imide, tributyl phosphorus, 86%; (V) hydrazine hydrate, ethanol, 60%; (VI) triethylamine, toluene, 69%; (VII) Lithium Aluminium Hydride, tetrahydrofuran (THF), 100%
Method 2 is by (Synthetic Communication, 37:3793-3799,2007) report, wherein PG
1=Boc, overall yield 36%, as shown in Equation 2:
Formula 2
Reagent and productive rate: (I) isopropyl chlorocarbonate, ammoniacal liquor; 60%; (II) trifluoroacetic anhydride, triethylamine, 85%; (III) LDA, 1-bromo-3-chloropropane, tetrahydrofuran (THF), 55%; (IV) hydrogen, Raney's nickel, ammoniacal liquor, 95%;
The synthetic method of this report has the following disadvantages: synthetic route is long, indivedual committed steps are all used LDA, need to carry out under low temperature (78 ℃) anhydrous and oxygen-free condition, reaction is comparatively harsh, and all there is the shortcoming that productive rate is low, product is difficult to purifying, overall yield is low in partial reaction.The feasibility that does not possess extensive preparation.
Summary of the invention:
The purpose of this invention is to provide a kind of efficient, mild condition, possess that extensive preparation is worth 1, the synthetic method of 7-diaza spiro [4,5] certain herbaceous plants with big flowers alkyl compound.It is long mainly to solve existing 1,7-diaza spiro [4,5] certain herbaceous plants with big flowers alkyl compound synthetic route, and yield is low, intermediate is difficult to purifying, severe reaction conditions, technical problem that can't scale operation.
Technical scheme of the present invention: be easy to prepare take N-PG-3-nitro piperidines as raw material, in alcoholic solution or acetonitrile, carry out reversal of the Michael addition with acrylate or propenal and obtain N-PG-3-(3-nitro piperidines-3-yl) propionic ester or N-PG-3-propionic aldehyde base-3-nitro piperidines, then above-mentioned product is in organic solvent, add catalyzer, the hydro-reduction ring closure reaction obtains with 1 of protecting group, 7-diaza-2-oxygen-spiral shell [4,5] certain herbaceous plants with big flowers alkane or with 1 of protecting group, 7-diaza spiro [4,5] certain herbaceous plants with big flowers alkane, with 1 of protecting group, 7-diaza-2-oxygen-spiral shell [4,5] certain herbaceous plants with big flowers alkane adds reductive agent and obtains with 1 of protecting group in organic solvent, 7-diaza spiro [4,5] certain herbaceous plants with big flowers alkane; Protecting group PG is a kind of in tertbutyloxycarbonyl, carbobenzoxy-(Cbz), benzyl, fluoroform acyl group, benzoyl, fluorenylmethoxycarbonyl, allyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, ethanoyl, pivaloyl group or the methoxyl methyl.
Concrete synthesis technique 1 of the present invention is summarized as follows:
In the above-mentioned technique; take the N-PG-3-piperidone as starting raw material; it is made oxime; be nitro piperidines A with oxime through oxidizing reaction again; it carries out Michael (Michael) addition reaction and obtains N-PG-3-(3-nitro piperidines-3-yl) propionic ester B in alcoholic solution or acetonitrile; B is then in organic solvent; add catalyzer; hydrogenation is closed ring and is obtained with 1 of protecting group 7-diaza-2-oxygen-spiral shell [4,5] certain herbaceous plants with big flowers alkane C; C is in organic solvent; add reductive agent and obtain 1 of target product band protecting group, 7-diaza spiro [4,5] certain herbaceous plants with big flowers alkane D.
In above-mentioned oxidation reaction process, oxygenant can be trifluoro Peracetic Acid, Peracetic Acid, metachloroperbenzoic acid, urea hydrogen peroxide, potassium hydrogen persulfate etc.The used alkali of oxidizing reaction can be sodium phosphate, and Sodium phosphate dibasic, alkali consumption are 1～5 times of equivalent of oxime, and temperature of reaction is 0～100 ℃.In Michael addition reaction process, the acrylate that adopts is methyl acrylate or ethyl propenoate, the alcoholic solution that adopts is a kind of in methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc., alcoholic solution or acetonitrile consumption are 10～30 times of equivalents of compd A, be preferably 10～20 times of equivalents, alkali is N, N, N-Three methyl Benzene first ammonium oxyhydroxide (Trition B), triethylamine, DIPEA (DIPEA) etc.; In hydro-reduction ring closure reaction process, organic solvent is selected a kind of in methyl alcohol, ethanol, propyl alcohol, the ethyl acetate, catalyzer is a kind of in Raney's nickel, palladium charcoal or the platinum dioxide, catalyst levels is 5～50% (mass percents) of Compound D, be preferably 8～16% (mass percents), reaction pressure is 10～50psi, is preferably 10～30psi, temperature of reaction is 15～65 ℃, is preferably 25～55 ℃.In the reduction reaction process, the solvent that adopts is tetrahydrofuran (THF), ether or dioxane, and reductive agent is borine-dimethyl sulphide mixture, borine-tetrahydrofuran (THF) mixture, Lithium Aluminium Hydride, sodium borohydride-boron trifluoride diethyl etherate, sodium borohydride-I
2, the system such as sodium borohydride-zinc chloride.The consumption of reductive agent is 1～5 times of equivalent of Compound C, is preferably 2～4 times of equivalents.
Concrete synthesis technique 2 of the present invention is summarized as follows:
In the above-mentioned technique 2; in alcoholic solution or acetonitrile, carry out the Michael addition reaction take N-PG-3-nitro piperidines as starting raw material and obtain N-PG-3-propionic aldehyde base-3-nitro piperidines; then in organic solvent; add catalyzer; the hydro-reduction ring closure reaction obtains with 1 of protecting group; 7-diaza spiro [4,5] certain herbaceous plants with big flowers alkane.
In above-mentioned reaction process, in Michael addition reaction process, the solvent that adopts is a kind of in methyl alcohol, ethanol, Virahol, the trimethyl carbinol, the acetonitrile etc., its consumption is 10～100 times of equivalents of compd E, be preferably 10～50 times of equivalents, alkali is Trition B, triethylamine, DIPEA etc.; In hydro-reduction ring closure reaction process, organic solvent is selected a kind of in methyl alcohol, ethanol, propyl alcohol, the ethyl acetate, catalyzer is a kind of in Raney's nickel, palladium charcoal or the platinum dioxide, catalyst levels is 5～50% (mass percents) of compound F 17-hydroxy-corticosterone, be preferably 8～16% (mass percents), reaction pressure is 10～55psi, is preferably 15～50psi, temperature of reaction is 25～65 ℃, is preferably 45～55 ℃;
The invention has the beneficial effects as follows: the present invention relates to a kind ofly 1, the improvement of 7-diaza spiro [4,5] certain herbaceous plants with big flowers alkane and derivatives class synthetic method thereof provides that a kind of reactions steps is few, productive rate is high, mild condition, possesses the synthetic method that extensive preparation is worth.This class drug template can be in conjunction with " combinatorial chemistry " technology platform, synthesize at short notice in a large number for the structurally-modified compound library of known aza toroid drug template, further screening can help to obtain the better medicine precursor compound of biological activity.In the technique of the present invention, reactions steps is few, only is the reaction of 3 steps; Overall yield is high; Mild condition is avoided using expensive and dangerous reagent, and technique is simple, can amplify scale production, is easy to industrial operation.
Embodiment:
The following example helps to understand the present invention, but is not limited to content of the present invention.
Embodiment 1
1.N-carbobenzoxy-(Cbz)-3-piperidines oxime is synthetic
Mixture N-carbobenzoxy-(Cbz)-3-piperidone (259 grams, 1.11 mole), oxammonium hydrochloride (234 grams, 3.33 mole) and sodium-acetate (272 grams, 3.33 it is complete mole) to stir the .TLC monitoring reaction of spending the night in ethanol (2000 milliliters) and water (600 milliliters) room temperature (10-30 ℃), concentrating under reduced pressure steams except ethanol, resistates ethyl acetate extraction, water washing, drying, concentrated crude product, column chromatography gets N-carbobenzoxy-(Cbz)-3-piperidines oxime colorless oil 146.65 grams (40%).
1H?NMR(400MHz，CDCl
3)d?ppm：δ7.258-7.362(m，5H)，δ5.134-5.154(m，2H)，δ4.094-4.147(m，2H)，δ3.533-3.580(m，2H)，δ2.603-2.636(m，1H)，δ2.364-2.396(m，1H)，δ1.744-1.772(m，2H).
2.1N-carbobenzoxy-(Cbz)-3-nitro piperidines is synthetic:
Urea hydrogen peroxide (47.3 gram, 0.6 mole) is dissolved in 400 milliliters the acetonitrile, and makes system be down to 0 ℃, then slowly drip the mixed solution of trifluoroacetic anhydride (88 grams, 0.42 mole) and 400 milliliters of acetonitriles.After dripping off, reaction system stirs 0 ℃ of lower continuation and obtained the trifluoro Peracetic Acid in 3 hours.Meanwhile, with N-carbobenzoxy-(Cbz)-3-piperidines oxime (52 grams, 0.21 mole), Sodium phosphate dibasic (165 grams, 1.16 mole) and the mixture heating up to 80 of 800 milliliters acetonitrile ℃, under this temperature, slowly drip the acetonitrile solution of firm ready-made trifluoro Peracetic Acid, drip off rear continuation and stir and spend the night hour.Reaction is cooled to room temperature, adds 2000 milliliters water and 500 milliliters ethyl acetate.Organic phase is respectively washed once with saturated sodium bicarbonate solution and saturated aqueous common salt, and anhydrous sodium sulfate drying filters, and is concentrated.Crude product obtains faint yellow oily thing 43 grams (77.6%) of N-carbobenzoxy-(Cbz)-3-nitro piperidines through the silicagel column purifying.
1H?NMR(400MHz，CDCl
3)d?ppm：δ7.330-7.411(m，5H)，δ5.126-5.194(m，2H)，δ4.221-4.440(m，2H)，δ3.571-3.799(m，2H)，δ3.201(s，1H)，δ2.168-2.312(m，2H)，δ1.756-1.790(m，1H)，δ1.521-1.581(m，2H).
2.2N-carbobenzoxy-(Cbz)-4-nitro piperidines is synthetic
Mixture N-carbobenzoxy-(Cbz)-3-piperidines oxime (115.9 grams, 0.467 mole), urea (265 grams, 4.2 mole) and Sodium phosphate dibasic (400 grams, 2.8 mole) (1.5 liters) reflux 0.5 hour in acetonitrile, then drip metachloroperbenzoic acid (284 gram, 1.4 moles) at the solution of acetonitrile (500 milliliters) in mixture, dropwised afterreaction liquid and continued back flow reaction 4 hours in 1.5 hours.TLC monitoring reaction is finished, reaction solution is down to room temperature, with saturated sodium sulfite aqueous solution cancellation metachloroperbenzoic acid, concentrating under reduced pressure boils off most of solvent, ethyl acetate extraction, salt solution washing, dry concentrated crude product, column chromatography get sterling N-carbobenzoxy-(Cbz)-4-nitro piperidines yellow oil 54.3 grams (44%).
2.3N-carbobenzoxy-(Cbz)-4-nitro piperidines is synthetic
Mixture N-carbobenzoxy-(Cbz)-3-piperidines oxime (58.01 grams, 0.234 mole), urea (132.5 grams, 2.1 mole) and Sodium phosphate dibasic (200 grams, 1.4 mole) (800 liters) reflux 0.5 hour in acetonitrile, then drip Peracetic Acid (53.25 gram, 0.7 mole) at the solution of acetonitrile (200 milliliters) in mixture, dropwised afterreaction liquid in 1.5 hours and continue back flow reaction and spend the night.TLC monitors reaction, reaction solution is down to room temperature, with saturated sodium sulfite aqueous solution cancellation Peracetic Acid acid, concentrating under reduced pressure boils off most of solvent, ethyl acetate extraction, salt solution washing, dry concentrated crude product, column chromatography get sterling N-carbobenzoxy-(Cbz)-4-nitro piperidines yellow oil 4.32 grams (7.0%).
3.1N-carbobenzoxy-(Cbz)-3-(3-nitro piperidines-3-yl) methyl propionate is synthetic:
N-carbobenzoxy-(Cbz)-3-nitro piperidines (54 grams, 0.20 mole) is dissolved in dropping Trition B methanol solution (32 milliliters) under the trimethyl carbinol (350 milliliters) room temperature, then adds methyl acrylate (17.5 grams, 0.20 mole).The reaction solution stirred overnight at room temperature.TLC monitors reaction, and reaction is finished, and concentrates and removes the trimethyl carbinol, and resistates is transferred to slightly acidic with hydrochloric acid soln.Ethyl acetate extraction, water washing, drying, concentrating under reduced pressure obtains crude product, and column chromatography for separation gets yellow oil N-carbobenzoxy-(Cbz)-3-(3-nitro piperidines-3-yl) ethyl propionate 38.0 grams (54.3%).
1H?NMR(400MHz，CDCl
3)d?ppm：δ7.257-7.355(m，5H)，δ5.097-5.223(m，2H)，δ4.421-4.455(m，4H)，δ3.605-3.788(m，2H)，δ3.182-3.329(m，2H)，δ2.158-2.472(m，5H)，δ1.662-1.837(m，3H).
3.2N-carbobenzoxy-(Cbz)-3-(3-nitro piperidines-3-yl) methyl propionate
With N-carbobenzoxy-(Cbz)-3-nitro piperidines (22 grams, 83.2 mmole) and triethylamine (0.84 gram, 8.32 mmoles) be dissolved in 200 milliliters the acetonitrile, drip propenal (7.46 grams under the room temperature, 133 mmoles) and the mixed solution of 20 milliliters acetonitrile, stirring is spent the night.TLC (petrol ether/ethyl acetate=1: 1) shows that raw material disappears, and reaction is finished.Concentrated, crude product gets N-carbobenzoxy-(Cbz)-3-(3-nitro piperidines-3-yl) methyl propionate oily matter 11.07 grams (38%) through the silicagel column purifying.
3.3N-carbobenzoxy-(Cbz)-3-(3-nitro piperidines-3-yl) methyl propionate
With N-carbobenzoxy-(Cbz)-3-nitro piperidines (19.12 grams, 83.2 mmole) and N, N-diisopropylethylamine (DIPEA) (1.075 grams, 8.32 mmole) be dissolved in 380 milliliters the acetonitrile, drip propenal (7.46 grams under the room temperature, 133 mmoles) and the mixed solution of 20 milliliters acetonitrile, stirring is spent the night.TLC (petrol ether/ethyl acetate=1: 1) shows that raw material disappears, and reaction is finished.Concentrated, crude product gets N-carbobenzoxy-(Cbz)-3-(3-nitro piperidines-3-yl) methyl propionate oily matter 10.2 grams (35.98%) through the silicagel column purifying.
4, N-carbobenzoxy-(Cbz)-1,7-diaza-2-oxygen-spiral shell [4,5] certain herbaceous plants with big flowers alkane synthetic
N-carbobenzoxy-(Cbz)-3-(3-nitro piperidines-3-yl) ethyl propionate (11.0 grams, 0.03 mole) be dissolved in 200 milliliters solvent (methyl alcohol, ethanol or propyl alcohol etc.), Raney's nickel (5.5 gram) under the pressure of 15-25psi in 20-35 ℃ of lower hydrogenation 8 hours.The TLC detection reaction finishes, and the filtration catalizer desolvation gets colorless oil N-carbobenzoxy-(Cbz)-1,7-diaza-2-oxygen-spiral shell [4,5] certain herbaceous plants with big flowers alkane 8.2 grams (95%).
1H?NMR：T000165412?TH01683-011-1C?CDCl3400MHz
1H?NMR(400MHz，CDCl
3)d?ppm：δ7.053-7.380(m，5H)，δ5.110-5.297(m，2H)，δ3.468-3.547(m，2H)，δ3.231-3.310(m，2H)，δ2.092-2.362(m，2H)，δ1.623-1.831(m，6H).
5.1N-carbobenzoxy-(Cbz)-1,7-diaza spiro [4,5] certain herbaceous plants with big flowers alkane synthetic
With N-carbobenzoxy-(Cbz)-1,7-diaza-2-oxygen-spiral shell [4,5] certain herbaceous plants with big flowers alkane (53 grams; 0.208 mole) be dissolved among the anhydrous tetrahydro furan THF (1000mL); be cooled to-10 ℃ to-5 ℃, then under nitrogen protection, drip borine-dimethyl sulphide solution (59.32 milliliters, 0.625 mole).Reaction solution is raised to 50-60 ℃ of reaction and spends the night, TLC monitoring reaction is finished, dilute hydrochloric acid solution is added drop-wise under 0 ℃ in the reaction solution and stirred 1 hour, ethyl acetate extraction, the salt solution washing, dry decompression desolventizes to get oily matter, becomes hydrochloride to get N-carbobenzoxy-(Cbz)-1,7-diaza spiro [4,5] certain herbaceous plants with big flowers alkane white solid 35 grams (60.86%).
1H?NMR(400MHz，CDCl
3)d?ppm：δ7.053-7.380(m，5H)，δ5.110-5.297(m，2H)，δ3.468-3.547(m，2H)，δ3.231-3.310(m，2H)，δ2.092-2.362(m，2H)，δ1.623-1.831(m，6H).
5.2N-carbobenzoxy-(Cbz)-1,7-diaza spiro [4,5] certain herbaceous plants with big flowers alkane synthetic
With N-carbobenzoxy-(Cbz)-1,7-diaza-2-oxygen-spiral shell [4,5] certain herbaceous plants with big flowers alkane (26.5 grams; 0.104 mole) be dissolved in 500 milliliters of the anhydrous tetrahydro furans; be cooled to-10 ℃ to-5 ℃, then under nitrogen protection, add Lithium Aluminium Hydride (9.88 grams, 0.261 mole) in batches.Reaction solution is warmed up to 50 ℃ of reactions and spends the night, TLC monitoring reaction is finished, dilute hydrochloric acid solution is added drop-wise under 0 ℃ in the reaction solution and stirred 1 hour, ethyl acetate extraction, the salt solution washing, dry decompression desolventizes to get oily matter, becomes hydrochloride to get N-carbobenzoxy-(Cbz)-1,7-diaza spiro [4,5] certain herbaceous plants with big flowers alkane white solid 28 grams (48.69%).
1H?NMR(400MHz，CDCl
3)d?ppm：δ7.053-7.380(m，5H)，δ5.110-5.297(m，2H)，δ3.468-3.547(m，2H)，δ3.231-3.310(m，2H)，δ2.092-2.362(m，2H)，δ1.623-1.831(m，6H).
Embodiment 2
The synthesized reference of N-tertbutyloxycarbonyl-4-nitro piperidines
Embodiment 1Operation steps 1 and 2.
1, N-tertbutyloxycarbonyl-3-(3-nitro piperidines-3-yl) methyl propionate is synthetic:
N-tertbutyloxycarbonyl-3-nitro piperidines (46 grams, 0.20 mole) is dissolved in dropping Trition B methanol solution (32 milliliters) under the trimethyl carbinol (350 milliliters) room temperature, then adds methyl acrylate (17.5 grams, 0.20 mole).The reaction solution stirred overnight at room temperature.TLC monitors reaction, and reaction is finished, and concentrates and removes the trimethyl carbinol, and resistates is transferred to slightly acidic with hydrochloric acid soln.Ethyl acetate extraction, water washing, drying, concentrating under reduced pressure obtains crude product, and column chromatography for separation gets yellow oil N-tertbutyloxycarbonyl-3-(3-nitro piperidines-3-yl) methyl propionate 40.17 grams (63.5%).
2, N-tertbutyloxycarbonyl-1,7-diaza-2-oxygen-spiral shell [4,5] certain herbaceous plants with big flowers alkane synthetic
N-tertbutyloxycarbonyl-3-(3-nitro piperidines-3-yl) methyl propionate (15.8 gram, 0.05 mole) is dissolved in methyl alcohol (300 milliliters), 5% palladium carbon (1.5 gram) under the pressure of 35-45psi in 25 ℃ of lower hydrogenations 8 hours.The TLC detection reaction finishes, and the filtration catalizer desolvation gets colorless oil N-tertbutyloxycarbonyl-1,7-diaza-2-oxygen-spiral shell [4,5] certain herbaceous plants with big flowers alkane 11.83 grams (93%).
3, N-tertbutyloxycarbonyl-1,7-diaza spiro [4,5] certain herbaceous plants with big flowers alkane synthetic
With N-tertbutyloxycarbonyl-1,7-diaza-2-oxygen-spiral shell [4,5] certain herbaceous plants with big flowers alkane (25.4 grams; 0.1 mole) be dissolved among the anhydrous tetrahydro furan THF (500 milliliters); be cooled to-10 ℃ to-5 ℃, then under nitrogen protection, drip borine-dimethyl sulphide solution (30 milliliters, 0.3 mole).Reaction solution is raised to 50-60 ℃ of reaction and spends the night, TLC monitoring reaction is finished, methyl alcohol was added drop-wise in the reaction solution return stirring 1 hour under 0 ℃, concentrating under reduced pressure, ethyl acetate extraction, salt solution washing, dry decompression desolventizes to get oily matter, become hydrochloride to get N-tertbutyloxycarbonyl-1,7-diaza spiro [4,5] certain herbaceous plants with big flowers alkane white solid 11.68 grams (48%).
Embodiment 3
The synthesized reference of N-carbobenzoxy-(Cbz)-3-nitro piperidines
Embodiment 1Operation steps 1 and 2.
1.N-carbobenzoxy-(Cbz)-3-propionic aldehyde base-3-nitro piperidines is synthetic
With N-carbobenzoxy-(Cbz)-3-nitro piperidines (10.99 grams, 41.6 mmole) and triethylamine (0.42 gram, 4.16 mmoles) be dissolved in 50 milliliters the acetonitrile, drip propenal (3.73 grams under the room temperature, 133 mmoles) and the mixed solution of 10 milliliters acetonitrile, stirring is spent the night.TLC (petrol ether/ethyl acetate=1: 1) shows that raw material disappears, and reaction is finished.Concentrated, crude product gets N-carbobenzoxy-(Cbz)-3-propionic aldehyde base-3-nitro piperidines yellow oily 6.5 grams (51.1%) through the silicagel column purifying.
2.N-carbobenzoxy-(Cbz)-1,7-diaza spiro [4,5] certain herbaceous plants with big flowers alkane synthetic
N-carbobenzoxy-(Cbz)-3-propionic aldehyde base-3-nitro piperidines (4.67 grams, 15.3 mmoles) and 1.0 gram Raney Ni are blended in 25 milliliters of ethanol, and at 20-25 ℃, hydrogen pressure 30Psi stirs and spends the night.TLC (petrol ether/ethyl acetate=1: 1) shows that raw material disappears, and reaction finishes.The reaction solution diatomite filtration, the concentrated N-carbobenzoxy-(Cbz)-1 that obtains of filtrate, 7-diaza spiro [4,5] certain herbaceous plants with big flowers alkane oily matter 2.6 grams (52.8%).
1H?NMR(400MHz，CDCl3))d?ppm：δ7.233-7.291(m，5H)，5.056(s，2H)，3.484-3.547(m，2H)，3.354-3.415(m，2H)，2.887-2.921(t，2H)，1.694-1.766(m，2H)，1.462-528(m，6H)；m/zfor?C16H22N2O2?275.2(M+H)+。
Claims (11)
1. one kind with 1 of protecting group, 7-diaza spiro [4,5] synthetic method of certain herbaceous plants with big flowers alkane, it is characterized in that the first step is reversal of the Michael addition, take N-PG-3-nitro piperidines as raw material, in alcoholic solution or acetonitrile, carry out reversal of the Michael addition with acrylate or propenal and obtain N-PG-3-(3-nitro piperidines-3-yl) propionic ester or N-PG-3-propionic aldehyde base-3-nitro piperidines, second step is the hydro-reduction ring closure reaction, and above-mentioned product adds catalyzer in organic solvent, hydrogenation is closed ring and is obtained with 1 of protecting group, 7-diaza-2-oxygen-spiral shell [4,5] certain herbaceous plants with big flowers alkane or with 1 of protecting group, 7-diaza spiro [4,5] certain herbaceous plants with big flowers alkane, the 3rd step reduction reaction, with 1 of protecting group, 7-diaza-2-oxygen-spiral shell [4,5] certain herbaceous plants with big flowers alkane is in organic solvent, add reductive agent and obtain with 1 of protecting group 7-diaza spiro [4,5] certain herbaceous plants with big flowers alkane;
Protecting group PG is a kind of in tertbutyloxycarbonyl, carbobenzoxy-(Cbz), benzyl, fluoroform acyl group, benzoyl, fluorenylmethoxycarbonyl, allyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, ethanoyl, pivaloyl group or the methoxyl methyl.
2. according to claim 1 a kind of with 1 of protecting group; 7-diaza spiro [4; 5] synthetic method of certain herbaceous plants with big flowers alkane; it is characterized in that; when carrying out reversal of the Michael addition with acrylate; acrylate is methyl acrylate or ethyl propenoate; described alcoholic solution is a kind of in methyl alcohol, ethanol, Virahol or the trimethyl carbinol; alcoholic solution or acetonitrile consumption are 0～30 times of equivalent of N-PG-3-nitro piperidinyl-1; reversal of the Michael addition need add alkali, and alkali is N, N; a kind of in N-Three methyl Benzene first ammonium oxyhydroxide, triethylamine or the DIPEA.
3. according to claim 2 a kind of with 1 of protecting group, the synthetic method of 7-diaza spiro [4,5] certain herbaceous plants with big flowers alkane is characterized in that, alcoholic solution or acetonitrile consumption are 0～20 times of equivalent of N-PG-3-nitro piperidinyl-1.
4. according to claim 1 a kind of with 1 of protecting group; 7-diaza spiro [4; 5] synthetic method of certain herbaceous plants with big flowers alkane; it is characterized in that; at N-PG-3-(3-nitro piperidines-3-yl) in the propionic ester hydro-reduction ring closure reaction process; organic solvent is selected a kind of in methyl alcohol, ethanol, propyl alcohol or the ethyl acetate; catalyzer is a kind of in Raney's nickel, palladium charcoal or the platinum dioxide; catalyst levels is N-PG-3-(3-nitro piperidines-3-yl) the propionic ester quality 5～50%; reaction pressure is 10～50 psi, and temperature of reaction is 15～65 ℃.
5. according to claim 4 a kind of with 1 of protecting group, the synthetic method of 7-diaza spiro [4,5] certain herbaceous plants with big flowers alkane; it is characterized in that; catalyst levels is N-PG-3-(3-nitro piperidines-3-yl) the propionic ester quality 8～16%, reaction pressure is 10～30 psi, temperature of reaction is 25～55 ℃.
6. according to claim 1 a kind of with 1 of protecting group; 7-diaza spiro [4; 5] synthetic method of certain herbaceous plants with big flowers alkane; it is characterized in that; in the reduction reaction process; the solvent that adopts is tetrahydrofuran (THF), ether or dioxane, and reductive agent is borine-dimethyl sulphide mixture, borine-tetrahydrofuran (THF) mixture, Lithium Aluminium Hydride, sodium borohydride-boron trifluoride diethyl etherate, sodium borohydride-I
2Or a kind of in sodium borohydride-zinc chloride, the consumption of reductive agent is with 1 of protecting group, 1～5 times of equivalent of 7-diaza-2-oxygen-spiral shell [4,5] certain herbaceous plants with big flowers alkane.
7. according to claim 6 a kind of with 1 of protecting group, the synthetic method of 7-diaza spiro [4,5] certain herbaceous plants with big flowers alkane is characterized in that the consumption of reductive agent is with 1 of protecting group, 2～4 times of equivalents of 7-diaza-2-oxygen-spiral shell [4,5] certain herbaceous plants with big flowers alkane.
8. according to claim 1 a kind of with 1 of protecting group; the synthetic method of 7-diaza spiro [4,5] certain herbaceous plants with big flowers alkane is characterized in that; when carrying out reversal of the Michael addition with propenal; described alcoholic solution is a kind of in methyl alcohol, ethanol, Virahol or the trimethyl carbinol, and alcoholic solution or acetonitrile consumption are 0～100 times of equivalent of N-PG-3-nitro piperidinyl-1, and reversal of the Michael addition need add alkali; alkali is N; N, a kind of in N-Three methyl Benzene first ammonium oxyhydroxide, triethylamine or the DIPEA.
9. according to claim 8 a kind of with 1 of protecting group, the synthetic method of 7-diaza spiro [4,5] certain herbaceous plants with big flowers alkane is characterized in that, alcoholic solution or acetonitrile consumption are 0～50 times of equivalent of N-PG-3-nitro piperidinyl-1.
10. according to claim 1 a kind of with 1 of protecting group; 7-diaza spiro [4; 5] synthetic method of certain herbaceous plants with big flowers alkane; it is characterized in that; in N-PG-3-propionic aldehyde base-3-nitro piperidines hydro-reduction ring closure reaction process; organic solvent is selected a kind of in methyl alcohol, ethanol, propyl alcohol or the ethyl acetate; catalyzer is a kind of in Raney's nickel, palladium charcoal or the platinum dioxide; catalyst levels is 5～50% of N-PG-3-propionic aldehyde base-3-nitro piperidines quality; reaction pressure is 10～55 psi, and temperature of reaction is 25～65 ℃.
11. according to claim 10 a kind of with 1 of protecting group, the synthetic method of 7-diaza spiro [4,5] certain herbaceous plants with big flowers alkane; it is characterized in that; catalyst levels is 8～16% of N-PG-3-propionic aldehyde base-3-nitro piperidines quality, and reaction pressure is 15～50 psi, and temperature of reaction is 45～55 ℃.
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| CN1946723A (en) * | 2004-04-06 | 2007-04-11 | 詹森药业有限公司 | Substituted diaza-spiro-[4.5|-decane derivatives and their use as neurokinin antagonists |
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Non-Patent Citations (4)
| Title |
|---|
| Ronald Grigg et al..X=Y-ZH Systems as Potential 1,3-dipoles. Part 21 Activation of the ZH Proton in Imines.《Tetrahedron》.1989,第45卷(第6期),1723-1746. |
| RonaldGriggetal..X=Y-ZHSystemsasPotential1 3-Dipoles. Part 39.X=Y-ZH Systems as Potential 1 |
| X=Y-ZH Systems as Potential 1,3-dipoles. Part 21 Activation of the ZH Proton in Imines;Ronald Grigg et al.;《Tetrahedron》;19891231;第45卷(第6期);1723-1746 * |
| X=Y-ZH Systems as Potential 1,3-Dipoles. Part 39.X=Y-ZH Systems as Potential 1,3-Dipoles. Part 39.Metallo-Azbmethine Ylides from Aliihatic Aldimines.Facile Regio- and Stereo-specific Cycloaddition Reactions.;Ronald Grigg et al.;《Tetrahedron》;19921231;第48卷(第47期);10431-10442 * |
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