CN102070633A - Method for synthesizing 1,8-diazaspiro[4.5]decane with protective group - Google Patents
Method for synthesizing 1,8-diazaspiro[4.5]decane with protective group Download PDFInfo
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- big flowers
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- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention relates to a method for preparing 1,8-diazaspiro[4.5]decane with a protective group, and mainly solves the technical problems that the conventional synthetic route for the 1,8-diazaspiro[4.5]decane is long, the yield is low, an intermediate is difficult to purify, reaction conditions are rigorous, and mass production cannot be performed. The method comprises the following steps of: performing Michael addition reaction on N-PG-4-nitropyridine serving as a raw material and acrylic ester in alcoholic solution or acetonitrile to obtain N-PG-4-propanal-4-nitropyridine; and adding a catalyst into the product in an organic solvent, and performing hydrogenation reduction ring-closing reaction to obtain the 1,8-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 8-diaza spiro [4,5] certain herbaceous plants with big flowers alkane.
Background technology:
1,8-diaza spiro [4,5] certain herbaceous plants with big flowers alkane derivatives is a kind of useful pharmaceutical intermediate, and the compound that the WO2007/025069A1 report contains this class core texture has the orexin receptor antagonists activity.Be mainly used in treatment and or prevent the medicinal application of following illness: eating disorder, obesity, diabetes homenergic metabolic imbalance disease; Somnopathy, schizophrenia, anxiety disorder and dysthymia disorders, circadian rhythm disorder.
For 1, the preparation of 8-diaza spiro [4,5] certain herbaceous plants with big flowers alkane derivatives, bibliographical information related compound method is as follows:
Method 1 is by WO2007/025069A1 report, wherein PG=Bn
As shown in Equation 1:
Formula 1
Reagent and productive rate: (I) sodium cyanide; (II) diallylamine; (III) 2-(2-bromotrifluoromethane)-1,3-dioxan, magnesium, tetrahydrofuran (THF); (IV) four triphenyl phosphorus palladiums, dimethyl barbituric acid; (V) sulfuric acid, methylene dichloride; (VI) acetic acid sodium borohydride, methylene dichloride; (VII) palladium hydroxide, methyl alcohol, 100%
Method 2 is by (J.Org.Chem 74:1304-1313,2009) report, wherein PG
1=Bn, PG
1=Boc, overall yield 30.5%, as shown in Equation 2:
Formula 2
Reagent and productive rate: (I) benzylamine, salt of wormwood, toluene, 97%; (II) allyl group bromination magnesium, toluene; 92% (III) hydrogen bromide, methyl alcohol; (IV) bromine ,-78 ℃, 90%; (V) hydrogen, palladium, Virahol, (Boc) 20,38%;
The synthetic method of this report has the following disadvantages: synthetic route is long, indivedual committed steps need to carry out under low temperature (78 ℃) condition, reaction is comparatively harsh, use the sodium cyanide of severe toxicity, 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 mass preparation.
Summary of the invention:
The purpose of this invention is to provide a kind of efficient, mild condition, possess 1 of band protecting group that mass preparation is worth, the synthetic method of 8-diaza spiro [4,5] certain herbaceous plants with big flowers alkyl compound.Mainly solve existingly 1,8-diaza spiro [4,5] certain herbaceous plants with big flowers alkyl compound synthetic route is long, and yield is low, intermediate is difficult to purifying, severe reaction conditions, technical problem that can't scale production.
Technical scheme of the present invention:
The present invention is a raw material with the N-PG-4-nitro piperidines that is easy to prepare; in alcoholic solution or acetonitrile, obtain N-PG-4-propionic aldehyde base-4-nitro piperidines by your (Michael) addition reaction of Mike with propenal; above-mentioned then product is in organic solvent; add catalyzer; the hydro-reduction ring closure reaction obtains with 1 of protecting group; 8-diaza spiro [4,5] certain herbaceous plants with big flowers alkane.
Concrete synthesis technique of the present invention is summarized as follows:
In the above-mentioned technology, be starting raw material, it is made oxime, by oxygenant oxime is oxidized to N-PG-4-nitro piperidines A again with the N-PG-4-piperidone.
In above-mentioned reaction process, protecting group PG of the present invention has tertbutyloxycarbonyl (Boc), carbobenzoxy-(Cbz) (Cbz), benzyl (Bn), fluoroform acyl group (CF
3CO), benzoyl, fluorenylmethoxycarbonyl, allyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, ethanoyl, pivaloyl group, methoxyl methyl etc.; In oxidation reaction process, oxygenant can be the trifluoro Peracetic Acid, Peracetic Acid, metachloroperbenzoic acid, urea hydrogen peroxide, a kind of in the potassium hydrogen persulfate.In Michael addition reaction process, the alcoholic solution that is adopted is a kind of in methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc., alcoholic solution or acetonitrile consumption are 5～100 times of equivalents of compd A, be preferably 10～50 times of equivalents, alkali is N, N, N-Three methyl Benzene first ammonium oxyhydroxide (Trition B), triethylamine, N, N-diisopropylethylamine (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 for use, catalyzer is a kind of in Raney's nickel (Raney Ni), palladium charcoal or the platinum dioxide, catalyst levels is 5～50% (mass percents) of compd B, be preferably 8～16% (mass percents), reaction pressure is 10～55psi, is preferably 10～50psi, temperature of reaction is 25～65 ℃, is preferably 45～55 ℃.
The invention has the beneficial effects as follows: the present invention is to existing 1,8-diaza spiro [4,5] certain herbaceous plants with big flowers alkane derivatives class synthetic method is improved, 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 aza toroid 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; The overall yield height; Mild condition is avoided using expensive and dangerous reagent, and technology is simple, and scalable 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-tertbutyloxycarbonyl-4-hydroxyl imido grpup piperidines is synthetic
Mixture N-tertbutyloxycarbonyl-4-piperidone (250g, 1.25mol), oxammonium hydrochloride (218g, 3.125mol) and salt of wormwood (346g, 2.5mol) in ethanol (2L), 50 ℃ were stirred 0.5 hour.TLC monitoring reaction is finished, reacting liquid filtering, and filtrate decompression concentrates, resistates is dissolved in ethyl acetate, water, salt solution washing respectively, drying, the crude product of concentrating under reduced pressure, petroleum ether obtain white solid N-tertbutyloxycarbonyl-4-hydroxyl imido grpup piperidines (193.5g, 72.3%).
1H?NMR(400MHz，CDCl3)d?ppm：δ3.512-3.555(m，4H)，2.594-2.625(m，2H)，2.316-2.346(m，2H)，1.468(s，9H)，
2.1N-tertbutyloxycarbonyl-4-nitro piperidines is synthetic
Mixture N-tertbutyloxycarbonyl-4-hydroxyl imido grpup piperidines (100 grams, 0.467 mole), urea (265 grams, 4.2 mole) and Sodium phosphate dibasic (400 grams, 2.8 (1.5 liters) reflux 0.5 hour in acetonitrile mole), drip then metachloroperbenzoic acid (284 gram, 1.4 moles) at the solution of acetonitrile (500 milliliters) in mixture, dropwised afterreaction liquid and continued back flow reaction 2 hours in 1.5 hours.TLC monitoring reaction is finished, reaction solution is reduced to room temperature, with saturated sodium sulfite aqueous solution cancellation metachloroperbenzoic acid, concentrating under reduced pressure boils off most of solvent, ethyl acetate extraction, the salt solution washing, dry spissated crude product, column chromatography get pure product N-tertbutyloxycarbonyl-4-nitro piperidines yellow oil 43.3g (40.3%).
1H?NMR(400MHz，CDCl3)d?ppm：δ4.465-4.393(m，1H)，3.957-3.987(m，2H)，2.894-2.961(m，2H)，2.122-2.164(m，2H)，1.930-2.026(m，2H)，1.397(s，9H)
2.2N-tertbutyloxycarbonyl-4-nitro piperidines is synthetic
Mixture N-tertbutyloxycarbonyl-4-hydroxyl imido grpup piperidines (50 grams, 0.234 mole), urea (132.5 grams, 2.1 mole) and Sodium phosphate dibasic (200 grams, 1.4 (800 liters) reflux 0.5 hour in acetonitrile mole), drip then 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 reduced 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 spissated crude product, column chromatography get pure product N-tertbutyloxycarbonyl-4-nitro piperidines yellow oil 5.91 grams (11%).
2.3N-tertbutyloxycarbonyl-4-nitro piperidines is synthetic
Urea hydrogen peroxide (47.3 gram, 0.6 mole) is dissolved in 400 milliliters the acetonitrile, and makes system reduce to 0 ℃, slowly drip the mixed solution of trifluoroacetic anhydride (88 grams, 0.42 mole) and 400 milliliters of acetonitriles then.After dripping off, reaction system continues stirring down at 0 ℃ and obtained the trifluoro Peracetic Acid in 3 hours.Meanwhile, with N-tertbutyloxycarbonyl-3-piperidines oxime (45.2 grams, 0.21 Sodium phosphate dibasic (165 grams mole),, 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 the back and continue to stir 3 hours.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 concentrates.Crude product obtains faint yellow oily thing 16.43 grams (34%) of N-tertbutyloxycarbonyl-3-nitro-pyrrole alkane through the silicagel column purifying.
1H?NMR(400MHz，CDCl3)d?ppm：δ4.465-4.393(m，1H)，3.957-3.987(m，2H)，2.894-2.961(m，2H)，2.122-2.164(m，2H)，1.930-2.026(m，2H)，1.397(s，9H)
3.1N-tertbutyloxycarbonyl-4-propionic aldehyde base-4-nitro piperidines is synthetic
With N-tertbutyloxycarbonyl-4-nitro piperidines (19.12 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.Concentrate, crude product gets N-tertbutyloxycarbonyl-4-propionic aldehyde base-4-nitro piperidines oily 17.67 grams (78%) through the silicagel column purifying.
3.2N-tertbutyloxycarbonyl-4-propionic aldehyde base-4-nitro piperidines is synthetic
With N-tertbutyloxycarbonyl-4-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.Concentrate, crude product gets N-tertbutyloxycarbonyl-4-propionic aldehyde base-4-nitro piperidines oily 13.5 grams (59.6%) through the silicagel column purifying.
3.2N-tertbutyloxycarbonyl-4-propionic aldehyde base-4-nitro piperidines is synthetic
With N-tertbutyloxycarbonyl-4-nitro piperidines (19.12 grams, 83.2 mmole) and N, N, N-Three methyl Benzene first ammonium oxyhydroxide (Trition B) (13 milliliters) is dissolved in 190 milliliters the trimethyl carbinol, drip propenal (7.46 grams under the room temperature, 133 mmoles) and the mixed solution of 20 milliliters the trimethyl carbinol, stirring is spent the night.TLC (petrol ether/ethyl acetate=1: 1) shows that raw material disappears, and reaction is finished.Concentrate, crude product gets N-tertbutyloxycarbonyl-4-propionic aldehyde base-4-nitro piperidines oily 8.84 grams (39%) through the silicagel column purifying.
4.N-tertbutyloxycarbonyl-1,8-diaza spiro [4,5] certain herbaceous plants with big flowers alkane synthetic
With N-tertbutyloxycarbonyl-4-propionic aldehyde base-4-nitro piperidines (12.0g, 88mmol) and 4.0 gram Raney Ni be blended in 250 milliliters the solvent (methyl alcohol, ethanol or propyl alcohol), at 25～50 ℃, hydrogen pressure 10～50Psi 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, filtrate concentrating obtains N-tertbutyloxycarbonyl-1, and 8-diaza spiro [4,5] certain herbaceous plants with big flowers alkane oily matter becomes the hydrochloride purifying to get white solid (8.9 grams～15.8 grams, 36.61%～65%).
1H?NMR(400MHz，CDCl3)d?ppm：δ9.300(s，1H)，3.624-3.660(d，2H)，3.166-3.203(m，4H)，1.921-1.958(m，2H)，1.840-1.859(m，2H)，1.700-1.765(m，4H)，1.370(s，9H)；m/z?for?C13H24N2O2?241.1(M+H)+
Embodiment 2
The synthesized reference of N-carbobenzoxy-(Cbz)-4-nitro piperidines
Embodiment 1Operation steps 1 and 2.
1.N-carbobenzoxy-(Cbz)-4-propionic aldehyde base-4-nitro piperidines is synthetic
With N-carbobenzoxy-(Cbz)-4-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.Concentrate, crude product gets N-carbobenzoxy-(Cbz)-4-propionic aldehyde base-4-nitro piperidines yellow oily 9.37 grams (73.5%) through the silicagel column purifying.
2.N-carbobenzoxy-(Cbz)-1,8-diaza spiro [4,5] certain herbaceous plants with big flowers alkane synthetic
N-carbobenzoxy-(Cbz)-4-propionic aldehyde base-4-nitro piperidines (9.37 grams, 30.6 mmoles) and 2.0 gram Raney Ni are blended in 50 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, filtrate concentrating obtains N-carbobenzoxy-(Cbz)-1,8-diaza spiro [4,5] certain herbaceous plants with big flowers alkane oily matter 6.4 grams (65%).
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/z?for?C16H22N2O2?275.2(M+H)+?。
Claims (7)
1. one kind with 1 of protecting group, 8-diaza spiro [4,5] synthetic method of certain herbaceous plants with big flowers alkane, it is characterized in that: with N-PG-4-nitro piperidines is raw material, obtains N-PG-4-propionic aldehyde base-4-nitro piperidines with propenal by reversal of the Michael addition in alcoholic solution or acetonitrile, and above-mentioned then product is in organic solvent, add catalyzer, obtain through the hydro-reduction ring closure reaction a kind of with 1 of protecting group, 8-diaza spiro [4,5] certain herbaceous plants with big flowers alkane;
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; 8-diaza spiro [4; 5] synthetic method of certain herbaceous plants with big flowers alkane and derivative thereof is characterized in that: in the reversal of the Michael addition process, alcoholic solution is a kind of in methyl alcohol, ethanol, Virahol or the trimethyl carbinol; alcoholic solution or acetonitrile consumption are 10～100 times of equivalents of N-PG-4-nitro piperidines; reversal of the Michael addition need add alkali, and alkali is N, N; N-Three methyl Benzene first ammonium oxyhydroxide, triethylamine or N, a kind of in the N-diisopropylethylamine.
3. according to claim 2 a kind of with 1 of protecting group, the synthetic method of 8-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-4-nitro piperidinyl-1.
4. according to claim 1 a kind of with 1 of protecting group; 8-diaza spiro [4; 5] synthetic method of certain herbaceous plants with big flowers alkane; it is characterized in that: in hydro-reduction ring closure reaction process; organic solvent is selected a kind of in methyl alcohol, ethanol, propyl alcohol or the ethyl acetate for use; catalyzer is a kind of in Raney's nickel, palladium charcoal or the platinum dioxide, and catalyst levels is 5～50% of N-PG-4-propionic aldehyde base-4-nitro piperidines mass percent.
5. according to claim 4 a kind of with 1 of protecting group, the synthetic method of 8-diaza spiro [4,5] certain herbaceous plants with big flowers alkane is characterized in that: in hydro-reduction ring closure reaction process, reaction pressure is 10～55psi, and temperature of reaction is 25～65 ℃.
6. according to claim 4 a kind of with 1 of protecting group, the synthetic method of 8-diaza spiro [4,5] certain herbaceous plants with big flowers alkane is characterized in that: catalyst levels is 8～16% of N-PG-4-propionic aldehyde base-4-nitro piperidines mass percent.
7. according to claim 5 a kind of with 1 of protecting group, the synthetic method of 8-diaza spiro [4,5] certain herbaceous plants with big flowers alkane is characterized in that: in hydro-reduction ring closure reaction process, reaction pressure is 10～50psi, and temperature of reaction is 45～55 ℃.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103130708A (en) * | 2011-12-01 | 2013-06-05 | 上海药明康德新药开发有限公司 | Preparing method of N-t-butyloxycarboryl-4-nitro piperidine |
| CN107383007A (en) * | 2017-06-29 | 2017-11-24 | 上海合全药业股份有限公司 | The preparation method of 1 benzyl 8 tert-butyl group 2 (methylol) diazaspiroalkanes decane dicarboxylic acid ester |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2006282955A1 (en) * | 2005-08-26 | 2007-03-01 | Merck & Co., Inc. | Diazaspirodecane orexin receptor antagonists |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103130708A (en) * | 2011-12-01 | 2013-06-05 | 上海药明康德新药开发有限公司 | Preparing method of N-t-butyloxycarboryl-4-nitro piperidine |
| CN107383007A (en) * | 2017-06-29 | 2017-11-24 | 上海合全药业股份有限公司 | The preparation method of 1 benzyl 8 tert-butyl group 2 (methylol) diazaspiroalkanes decane dicarboxylic acid ester |
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Effective date of registration: 20170220 Address after: 200131 Shanghai City, Pudong New Area Waigaoqiao Free Trade Zone Foote Road No. 288 Patentee after: Shanghai Yaoming Kangde New Medicine Development Co., Ltd. Patentee after: Tianjin Yaoming Kangde New Medicine Development Co., Ltd. Patentee after: Shanghai SynTheAll Pharmaceutical Co., Ltd. Address before: 200131 Shanghai City, Pudong New Area Waigaoqiao Free Trade Zone Foote Road No. 288 Patentee before: Shanghai Yaoming Kangde New Medicine Development Co., Ltd. Patentee before: Tianjin Yaoming Kangde New Medicine Development Co., Ltd. |