CN102070640A - Method for synthesizing 1,7-diazaspiro[4.5]nonane and derivatives thereof - Google Patents
Method for synthesizing 1,7-diazaspiro[4.5]nonane and derivatives thereof Download PDFInfo
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- RYARLZZMEHTICK-VURMDHGXSA-N CNCN(CC1)C/C1=N\O Chemical compound CNCN(CC1)C/C1=N\O RYARLZZMEHTICK-VURMDHGXSA-N 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
The invention relates to a method for industrially preparing 1,7-diazaspiro[4.5]nonane derivatives, and mainly solves the technical problems of multiple reaction steps and low yield of the conventional synthetic method. The method comprises the following steps of: performing reaction on the conventional and readily available pyrrolidone with an amino-protecting group (PG1) serving as a raw material and hydroxylamine hydrochloride to obtain pyrrolidine oxime with the amino-protecting group (PG1); oxidizing the pyrrolidine oxime with the amino-protecting group (PG1) into 3-nitro-pyrrole with the amino-protecting group (PG1) by using trifluoroperacetic acid; performing Michael addition on the 3-nitro-pyrrole with the amino-protecting group (PG1) to obtain 3-propanal-3-nitropyrrolidine with the amino-protecting group (PG1); and adding a catalyst into the 3-propanal-3-nitropyrrolidine with the amino-protecting group (PG1) in an organic solvent, and hydrogenating to obtain the target product of 1,7-diazaspiro[4.5]nonane. The compounds can be further subjected to acylation or alkylation reaction to form 1,7-diazaspiro[4.5]nonane medicine templates.
Description
Technical field:
The present invention relates to a kind of 1, the preparation method of 7-diaza spiro [4,5] nonane and derivative thereof.
Background technology:
1,7-diaza spiro [4,5] nonane derivatives is a kind of useful pharmaceutical intermediate, and the compound that contains this class core texture has wide biological activity.Document J.Med.Chem.1990, (33), once reported in 2270 that compound 1 was a kind of microbiotic of excellent performance, as the derivative of quinolone antibiotics such as norfloxicin, sparfloxacin, enoxacin and Ciprofloxacin, introduce the alpha-aza toroid substituting group and can obviously improve physiologically active.Document Collect.Czech.Chem.Commun.1982, (47), report compound 2 can obviously improve the optical activity of peptide in 950.Document Org.Lett.2007, (9), 3519 have reported that compound 3 this diamine spirocyclic compounds are the very important medical compoundss of a class.Document Syn.Comm.2007, (37), 3793, Tetrahedron 2007, (63) 9235 and Tetrahedron Letters 2006, (47) have reported that compound 2 and 4 this diamine spirocyclic compounds can follow most of bioactive molecules combination in 3005, being a class important compound in the modern organic synthesis, also is one of important research strategy that is used for Modern Pharmaceutical Chemistry research.
J.Med.Chem.1990，33，2270?Collect.Czech.Chem.Commun.1982，(47)，950Org.Lett.2007，(9)，3519
Syn.Comm.2007，(37)，3793
1,7-diaza spiro [4,5] nonane derivatives can be in conjunction with " combinatorial chemistry " technology platform, make the researchist be " template " with main structure, synthesize a large amount of at short notice at the structurally-modified compound library of this class drug template, by further efficient screening, might obtain having similar active even specificity is stronger, toxicity is littler prodrug, shorten the construction cycle of new drug greatly and reduce cost of development.
For 1, the preparation of 7-diaza spiro [4,5] nonane derivatives, the main method of bibliographical information comprises:
Method 1 is by (J.Med.Chem.1990,33,2270) report, wherein PG
1=Bn, R
1=Me, R
2=H, overall yield 7%, as shown in Equation 1:
Formula 1
Reagent and productive rate: (i) diisopropylamine lithium (LDA), bromoacetonitrile, 40%; (ii) hydrogen/Raney's nickel, 90%; (iii) toluene, 36%; (iv) lithium aluminum hydride, 55%.
Method 2 is reported by (Collect.Czech.Chem.Commun.1982,47,950), overall yield 13%, as shown in Equation 2:
Formula 2
Reagent and productive rate: (i) sodium-acetate, oxammonium hydrochloride, 86%; (ii) polyphosphoric acid, 83%; (iii) sodium periodate, 52%; (iv) ammonium chloride, potassium cyanide, ammoniacal liquor, 76%; (v) 190 spend 1.3KPa, 60%; (vi) red aluminium, 80%.
Method 3 is by (Syn.Comm.2007, (37), 3793) report, PG=Boc wherein, and overall yield 25%, as shown in Equation 3:
Formula 3
Reagent and productive rate: (i) Vinyl chloroformate, ammoniacal liquor, 60%; (ii) TFAA, triethylamine, 85%; (iii) LDA, 1-chloro-2-monobromethane, 55%; (iv) Raney Ni, hydrogen, ammoniacal liquor, 90%.
Method 4 is by (Org.Lett.2007, (9), 3519) report, PG=Cbz wherein, and overall yield 30%, as shown in Equation 4:
Formula 4
Reagent and productive rate: (i) a) chloroformic acid benzyl ester, tetrahydrofuran (THF), b) thionyl chloride, c) diethylamine, compound 2,49%; (ii) tosic acid, tetrahydrofuran (THF) 86%; (iii) sodium periodate, 90%; (iv) DBU, compound 6,92%; (v) Lithium Aluminium Hydride (5 equivalent), 86%.
Method 5 is reported by (Tetrahedron 2007, (63) 9235 and Tetrahedron Letters 2006, (47), 3005), overall yield 5.6%, as shown in Equation 5:
Formula 5
Reagent and productive rate: (i) thionyl chloride, methyl alcohol, 94%; (ii) (Boc)
2O, DMAP, 71%; (iii) LHDMS, allyl bromide 98,80%; (iv) perosmic anhydride, sodium periodate, 74%; (v) sodium borohydride, R-phenylethylamine; (vi) sodium amide, toluene, 30% liang of step; (vii) trifluoroacetic acid, potassium hydroxide, 89%; (viii) Lithium Aluminium Hydride, 53%.
Method 6 is reported by patent (WO 2,009,091,561), overall yield 9.7%, as shown in Equation 6:
Formula 6
Reagent and productive rate: (i) thionyl chloride, a-methylbenzylamine, triethylamine, methylene dichloride, 41%; Compound 1 is with reference to Heterocycles1994, and (37), 245 syntheticly do not provide any data; (ii) ozone, dimethyl sulphide, triethyl silicon, methylene dichloride, 42%; (iii) Lithium Aluminium Hydride, tetrahydrofuran (THF), 61%; (iv) palladium hydroxide/carbon, methyl alcohol, 84%.
Method 7 is reported by patent (WO 2,006,023,630), overall yield 53%, as shown in Equation 7:
Formula 7
Reagent and productive rate: (i) n-Butyl Lithium, Diisopropylamine, nitroethylene (with reference to J.Org.Chem.1980, (45), 1185 preparations, explosive, 80%), tetrahydrofuran (THF), 76.3%; (ii) Raney's nickel, ethanol, 93.1%; (iii) Lithium Aluminium Hydride, tetrahydrofuran (THF), 95.7%.
Related committed step ring closure reaction in the document, or utilize the aminolysis (method 1 of ester, 5,7), or utilize the condensation (method 6) of aldehyde and acid amides, or utilize the condensation (method 2) of carboxylic acid and amine, or utilize the replacement (method 3) of haloalkane and amine, or the functional group that utilizes the ring expansion (method 4) of acid amides, this several method all need carry out multistep introduces and conversion, increased reactions steps, and all there is the low shortcoming of productive rate in ring closure reaction.Thereby on whole synthetic route, the whole bag of tricks reactions steps that document is reported many (needing the reaction of 5～8 steps usually), overall yield is low (to be generally 5～30%, method 7 yields 53%, but the explosive danger of agents useful for same is too big), do not possess the feasibility of mass preparation.
Summary of the invention:
The purpose of this invention is to provide a kind of efficient, mild condition, possess that mass preparation is worth a kind of 1, the synthetic method of 7-diaza spiro [4,5] nonane derivatives, the technical issues that need to address are: former synthetic method reactions steps is many, and productive rate is low.
In the technical solution of the present invention: a kind of 1,7-diaza spiro [4,5] nonane derivatives, its chemical structural formula is as follows:
Compound I
Wherein, PG
1And PG
2Be the substituting group on the nitrogen-atoms, be hydrogen atom (H), tertbutyloxycarbonyl (Boc), carbobenzoxy-(Cbz) (Cbz), benzyl (Bn) etc., PG herein
1With PG
2Can be the same or different.
Alpha-aza toroid drug template shown in more related above Compound I in the embodiment of the invention, including, but not limited to: (a)-(f) etc.
The present invention will improve the synthetic method of above-mentioned drug template.Synthesis technique specifically is summarized as follows:
In the above-mentioned technology, when being carried out to oximation reaction, will have amido protecting group (PG
1) pyrrolidone A be dissolved in the second alcohol and water, successively add basic cpd, oxammonium hydrochloride, obtain amido protecting group (PG
1) pyrrolidine oximes (B); Compd B is in Sodium phosphate dibasic and acetonitrile, and oxidized dose is oxidized to amido protecting group (PG
1) 3-nitro-pyrroles (C); Compound C gets product amido protecting group (PG through your addition of Mike
1) 3-propionic aldehyde base-3-nitro-pyrrole alkane D; Compound D adds catalyzer in organic solvent, hydrogenation obtains target product 1,7-diaza spiro [4,5] nonane E; Compd E is further derivatize also, i.e. acylations or alkylation obtains more target product 1,7-diaza spiro [4,5] nonane derivatives F.
In becoming the oxime reaction process, the basic cpd that is adopted is a salt of wormwood, yellow soda ash, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium phosphate, sodium-acetate, a kind of in the Potassium ethanoate, its consumption is 2～8 times of equivalents of compd A, is preferably 3～5 times of equivalents, temperature when adding basic cpd is-20～30 ℃, is preferably 10～30 ℃; The consumption of oxammonium hydrochloride is 2～8 times of equivalents of compd A, is preferably 3～5 times of equivalents; In oxidation reaction process, oxygenant can be trifluoro Peracetic Acid, Peracetic Acid, metachloroperbenzoic acid, urea hydrogen peroxide, potassium hydrogen persulfate etc., consumption are 1～5 times of equivalent of compd B, be preferably 2～4 times of equivalents, temperature of reaction is 50～100 ℃, is preferably 70～90 ℃.In the reversal of the Michael addition process, the consumption of propenal is 1～3 times of equivalent of Compound C, is preferably 1.5～2 times of equivalents, and the consumption of triethylamine is 0.1～1 times of equivalent of Compound C, is preferably 0.1～0.4 times of equivalent; In reduction ring closure reaction process, organic solvent is selected a kind of in methyl alcohol, ethanol, ethyl acetate or the acetone for use, catalyzer is a kind of in Raney's nickel, palladium charcoal or the platinum dioxide, its consumption is 5～20% (mass percents) of Compound D, be preferably 8～16% (mass percents), reaction pressure is 30～60psi, is preferably 45～50psi, temperature of reaction is 40～65 ℃, is preferably 45～55 ℃; In the derivative reaction process, acyl chlorides, alkylating reagent, the consumption of acid anhydrides are 1～3 times of equivalent of compd E, are preferably 1.5～2 times of equivalents.
The invention has the beneficial effects as follows: synthetic method reactions steps of the present invention is few, productive rate is high, mild condition, possesses mass preparation and is worth.Technology of the present invention is simple, and reactions steps only is the reaction of 4 steps, and overall yield Gao Keda 40～50%, avoid using expensive and dangerous reagent, and scalable scale is carried out, and is easy to industrial operation.This class drug template that the present invention obtains can be in conjunction with " combinatorial chemistry " technology platform, synthesize in a large number at the structurally-modified compound library of known alpha-aza toroid drug template at short notice, further screening can help to obtain biological activity better medicament precursor compound.
Embodiment:
The following example helps to understand the present invention, but is not limited to content of the present invention.
Embodiment 1
1.1N-tertbutyloxycarbonyl-3-pyrrolidine oximes is synthetic
With N-tertbutyloxycarbonyl-3-pyrrolidone (200g, 1.08mol) be dissolved in the mixing solutions of 2.0L ethanol and 680mL water, add sodium-acetate (264g successively in the-20--10 ℃ of downhill reaction system, 3.24mol) and oxammonium hydrochloride (224g, 3.24mol), be warming up to 10-30 ℃ of stirring after adding and spend the night.TLC (volume percent of petrol ether/ethyl acetate=5: 1) shows that raw material disappears, and reaction is finished.Ethanol in the reaction solution is spun off, add 2.0L water and use ethyl acetate extraction twice, each 800mL.Organic phase is merged, and with the saturated common salt washing once, anhydrous sodium sulfate drying filters, and concentrates.Crude product petroleum ether twice, vacuum-drying obtains N-tertbutyloxycarbonyl-3-pyrrolidine oximes (white solid, 198g, 91.7%).
1H?NMR：(400MHz，CDCl
3)δ4.16-4.34(t，2H)，3.20(br，1H)，3.02(s，2H)，2.55-2.68(t，2H)，1.38(s，9H)
MS(m/z)：201(M+1)
1.2N-tertbutyloxycarbonyl-3-pyrrolidine oximes is synthetic
With N-tertbutyloxycarbonyl-3-pyrrolidone (200g, 1.08mol) be dissolved in the mixing solutions of 2.0L ethanol and 680mL water, under the room temperature 10-30 ℃ in reaction system, add successively sodium-acetate (264g, 3.24mol) and oxammonium hydrochloride (224g, 3.24mol), stirring is spent the night.TLC (volume percent of petrol ether/ethyl acetate=5: 1) shows that raw material disappears, and reaction is finished.Ethanol in the reaction solution is spun off, add 2.0L water and use ethyl acetate extraction twice, each 800mL.Organic phase is merged, and with the saturated common salt washing once, anhydrous sodium sulfate drying filters, and concentrates.Crude product petroleum ether twice, vacuum-drying obtains N-tertbutyloxycarbonyl-3-pyrrolidine oximes (white solid, 198g, 91.7%).
1H?NMR：(400MHz，CDCl
3)δ4.16-4.34(t，2H)，3.20(br，1H)，3.02(s，2H)，2.55-2.68(t，2H)，1.38(s，9H)
MS(m/z)：201(M+1)
1.3N-tertbutyloxycarbonyl-3-pyrrolidine oximes is synthetic
With N-tertbutyloxycarbonyl-3-pyrrolidone (200g, 1.08mol) be dissolved in the mixing solutions of 2.0L ethanol and 680mL water, add sodium hydroxide (129.6g successively in the-20--10 ℃ of downhill reaction system, 3.24mol) and oxammonium hydrochloride (224g, 3.24mol), be warming up to 10-30 ℃ of stirring after adding and spend the night.TLC (volume percent of petrol ether/ethyl acetate=5: 1) shows that raw material disappears, and reaction is finished.Ethanol in the reaction solution is spun off, add 2.0L water and use ethyl acetate extraction twice, each 800mL.Organic phase is merged, and with the saturated common salt washing once, anhydrous sodium sulfate drying filters, and concentrates.Crude product petroleum ether twice, vacuum-drying obtains N-tertbutyloxycarbonyl-3-pyrrolidine oximes (white solid, 120g, 55.7%).
1H?NMR：(400MHz，CDCl
3)δ4.16-4.34(t，2H)，3.20(br，1H)，3.02(s，2H)，2.55-2.68(t，2H)，1.38(s，9H)
MS(m/z)：201(M+1)
2.1, N-tertbutyloxycarbonyl-3-nitro-pyrrole alkane synthetic
With urea hydrogen peroxide (56.4g 0.6mol) is dissolved in the 400mL acetonitrile, and makes system reduce to 0 ℃, slowly drip then trifluoroacetic anhydride (115.5g, 0.55mol) and the mixed solution of 400mL acetonitrile.After dripping off, reaction system continues stirring down at 0 ℃ and obtained the trifluoro Peracetic Acid in 30 minutes.Meanwhile, with N-tertbutyloxycarbonyl-3-pyrrolidine oximes (50g, 0.25mol), Sodium phosphate dibasic (197.4g, 1.4mol) and the mixture heating up to 80 of 800mL acetonitrile ℃, under this temperature, slowly drip the acetonitrile solution of firm ready-made trifluoro Peracetic Acid, drip off the back and continue to stir two hours.Reaction is cooled to room temperature (10-30 ℃), adds 2.0L water and 500mL 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 N-tertbutyloxycarbonyl-3-nitro-pyrrole alkane (faint yellow solid, 38g, 70%) through the silicagel column purifying.
1H?NMR：(400MHz，CDCl
3)δ3.81-4.05(m，3H)，3.30-3.40(m，2H)，2.04-2.29(m，2H)，1.40(s，9H)
MS(m/z)：218(M+1)
2.2, N-tertbutyloxycarbonyl-3-nitro-pyrrole alkane synthetic
Mixture N-tertbutyloxycarbonyl-3-pyrrolidine oximes (50g, 0.25mol), urea (132.5g, 2.1mol) and Sodium phosphate dibasic (200g, 1.4mol) (1.5L) reflux 0.5 hour in acetonitrile, drip then metachloroperbenzoic acid (142g, 0.7mol) at the solution of acetonitrile (500mL) 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, salt solution washing, dry spissated crude product, column chromatography gets pure product N-tertbutyloxycarbonyl-3-nitro-pyrrole alkane (faint yellow solid, 19g, 35%).
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)
2.3, N-tertbutyloxycarbonyl-3-nitro-pyrrole alkane synthetic
Mixture N-tertbutyloxycarbonyl-3-pyrrolidine oximes (50g, 0.25mol), urea (132.5g, 2.1mol) and Sodium phosphate dibasic (200g, 1.4mol) (1.5L) reflux 0.5 hour in acetonitrile, drip then Peracetic Acid (53.2g, 0.7mol) at the solution of acetonitrile (500mL) 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, salt solution washing, dry spissated crude product, column chromatography gets pure product N-tertbutyloxycarbonyl-3-nitro-pyrrole alkane (faint yellow solid, 5g, 9%).
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, N-tertbutyloxycarbonyl-3-propionic aldehyde base-3-nitro-pyrrole alkane is synthetic
With N-tertbutyloxycarbonyl-3-nitro-pyrrole alkane (18g, 83.2mmol) and triethylamine (0.84g 8.32mmol) is dissolved in the 60mL acetonitrile, and (7.46g, 133mmol) and the mixed solution of 10mL acetonitrile, stirring is spent the night to drip propenal under the room temperature.TLC (volume percent of petrol ether/ethyl acetate=1: 1) shows that raw material disappears, and reaction is finished.Concentrate, crude product gets N-tertbutyloxycarbonyl-3-propionic aldehyde base-3-nitro-pyrrole alkane (yellow oily, 18g, 80%) through the silicagel column purifying.
1H?NMR：(400MHz，CDCl
3)δ9.72(t，1H)，3.77-4.02(m，2H)，3.30-3.40(m，2H)，2.35-2.43(m，2H)，2.10-2.20(m，2H)，2.00-2.25(m，2H)，1.35(s，9H)
MS(m/z)：273(M+1)
4.1,1,7-diaza spiro [4,5] nonane synthetic
(12.0g 44mmol) is blended in the methyl alcohol with 2.0 Cray Buddhist nun (Raney) Ni, and at 50 ℃, hydrogen pressure 50Psi stirs and spends the night with N-tertbutyloxycarbonyl-3-propionic aldehyde base-3-nitro-pyrrole alkane.TLC (volume percent of petrol ether/ethyl acetate=1: 1) shows that raw material disappears, and reaction finishes.The reaction solution diatomite filtration, filtrate concentrating obtains 1,7-diaza spiro [4,5] nonane (yellow oily, 9.5g, 95%)
1H?NMR：(400MHz，CDCl
3)δ3.27-3.52(m，4H)，3.44(br，1H)，2.70-2.80(m，2H)，1.50-1.78(m，6H)，1.43(s，9H)
MS(m/z)：227(M+1)
4.2,1,7-diaza spiro [4,5] nonane synthetic
(12.0g 44mmol) is blended in the methyl alcohol with 2.0 Cray Buddhist nun (Raney) Ni, and at 30 ℃, hydrogen pressure 30Psi stirred two days with N-tertbutyloxycarbonyl-3-propionic aldehyde base-3-nitro-pyrrole alkane.TLC (volume percent of petrol ether/ethyl acetate=1: 1) shows that raw material disappears, and reaction finishes.The reaction solution diatomite filtration, filtrate concentrating obtains 1,7-diaza spiro [4,5] nonane (yellow oily, 7.5g, 75%)
1H?NMR：(400MHz，CDCl
3)δ3.27-3.52(m，4H)，3.44(br，1H)，2.70-2.80(m，2H)，1.50-1.78(m，6H)，1.43(s，9H)
MS(m/z)：227(M+1)
Embodiment 2
1,7-diaza spiro [4,5] nonane derivatives synthetic
With compound 5 (9.0g, 39.8mmol) and triethylamine (8.05g 79.6mmol) is dissolved in the 100mL anhydrous tetrahydro furan, slowly drip under 0 ℃ chloroformic acid benzyl ester (8.15g, 47.8mmol) and the mixed solution of 20mL anhydrous tetrahydro furan.Stir under the reaction system room temperature and spend the night.TLC (volume percent of methylene chloride=10: 1) shows that raw material disappears, and reaction finishes.Reaction mixture is filtered, and filtrate concentrating obtains crude product, obtains compound 6 (white solid, 13g, 90%) through the silicagel column purifying
1H?NMR：(400MHz，CDCl
3)δ7.22-7.48(m，5H)，4.94(s，2H)，3.65(d，1H)，3.32-3.42(m，5H)，1.82-1.92(m，1H)，1.39-1.65(m，5H)，1.44(s，9H)MS(m/z)：361(M+1)
Embodiment 3
1.N-carbobenzoxy-(Cbz)-3-pyrrolidine oximes is synthetic
With N-carbobenzoxy-(Cbz)-3-pyrrolidone (200g, 0.912mol) be dissolved in the mixing solutions of 1.7L ethanol and 570mL water, add successively in the room temperature downhill reaction system sodium-acetate (132.8g, 1.62mol) and oxammonium hydrochloride (189g, 2.73mol), stirring is spent the night.TLC (volume percent of petrol ether/ethyl acetate=5: 1) shows that raw material disappears, and reaction is finished.Ethanol in the reaction solution is spun off, add 2.0L water and use ethyl acetate extraction twice, each 800mL.Organic phase is merged, and with the saturated common salt washing once, anhydrous sodium sulfate drying filters, and concentrates.Crude product petroleum ether twice, vacuum-drying obtains N-carbobenzoxy-(Cbz)-3-pyrrolidine oximes (white solid, 190g, 89%).
1H?NMR：(400MHz，CDCl
3)δ7.38-7.47(m，5H)，5.09(s，2H)，4.09-4.22(t，2H)，3.04(s，2H)，2.54-2.60(t，2H)，2.25(br，1H)
MS(m/z)：235(M+1)
2.N-carbobenzoxy-(Cbz)-3-nitro-pyrrole alkane is synthetic
With urea hydrogen peroxide (47.4g 0.504mol) is dissolved in the 336mL acetonitrile, and makes system reduce to 0 ℃, slowly drip then trifluoroacetic anhydride (97.0g, 0.462mol) and the mixed solution of 336mL acetonitrile.After dripping off, reaction system continues stirring down at 0 ℃ and obtained the trifluoro Peracetic Acid in 30 minutes.Meanwhile, with N-carbobenzoxy-(Cbz)-3-pyrrolidine oximes (50g, 0.213mol), Sodium phosphate dibasic (165.8g, 1.18mol) and the mixture heating up to 80 of 672mL acetonitrile ℃, under this temperature, slowly drip the acetonitrile solution of firm ready-made trifluoro Peracetic Acid, drip off the back and continue to stir two hours.Reaction is cooled to room temperature, adds 2.0L water and 500mL 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 N-carbobenzoxy-(Cbz)-3-nitro-pyrrole alkane (faint yellow solid, 38.4g, 72%) through the silicagel column purifying.
1H?NMR：(400MHz，CDCl
3)δ7.37-7.45(m，5H)，5.13(s，2H)，3.75-4.03(m，3H)，3.33-3.45(m，2H)，1.98-2.25(m，2H)
MS(m/z)：252(M+1)
3.N-carbobenzoxy-(Cbz)-3-propionic aldehyde base-3-nitro-pyrrole alkane is synthetic
With N-carbobenzoxy-(Cbz)-3-nitro-pyrrole alkane (20g, 79.9mmol) and triethylamine (0.81g 7.99mmol) is dissolved in the 60mL acetonitrile, and (7.16g, 127mmol) and the mixed solution of 10mL acetonitrile, stirring is spent the night to drip propenal under the room temperature.TLC (volume percent of petrol ether/ethyl acetate=1: 1) shows that raw material disappears, and reaction is finished.Concentrate, crude product gets N-carbobenzoxy-(Cbz)-3-propionic aldehyde base-3-nitro-pyrrole alkane (yellow solid, 20g, 82%) through the silicagel column purifying.
1H?NMR：(400MHz，CDCl
3)δ9.80(t，1H)，7.33-7.45(m，5H)，5.20(s，2H)，3.75-4.08(m，2H)，3.25-3.39(m，2H)，2.37-2.42(m，2H)，2.11-2.18(m，2H)，2.04-2.21(m，2H)
MS(m/z)：307(M+1)
4.1,7-diaza spiro [4,5] nonane synthetic
(12.3g 40mmol) is blended in the methyl alcohol with 2.0 Cray Buddhist nun (Raney) Ni, and in room temperature, hydrogen pressure 30Psi stirs and spends the night with N-carbobenzoxy-(Cbz)-3-propionic aldehyde base-3-nitro-pyrrole alkane.TLC (volume percent of petrol ether/ethyl acetate=1: 1) shows that raw material disappears, and reaction finishes.The reaction solution diatomite filtration, filtrate concentrating obtains 1,7-diaza spiro [4,5] nonane (yellow solid, 9.7g, 93%)
1H?NMR：(400MHz，CDCl
3)δ7.25-7.48(m，5H)，4.89(s，2H)，3.17-3.41(m，4H)，3.05(br，1H)，2.71-2.79(m，2H)，1.65-1.79(m，6H)
MS(m/z)：261(M+1)
Embodiment 4
1,7-diaza spiro [4,5] nonane derivatives synthetic
With compound 11 (9.0g, 34.6mmol) and DMAP (0.42g 3.46mmol) is dissolved in the 100mL anhydrous tetrahydro furan, slowly drip under 0 ℃ Boc2O (9.06g, 41.6mmol) and the mixed solution of 20mL anhydrous tetrahydro furan.Stir under the reaction system room temperature and spend the night.TLC (volume percent of methylene chloride=10: 1) shows that raw material disappears, and reaction finishes.Reaction mixture is filtered, and filtrate concentrating obtains crude product, obtains compound 12 (white solid, 12g, 96%) through the silicagel column purifying
1H?NMR：(400MHz，CDCl
3)δ7.22-7.48(m，5H)，5.34(s，2H)，3.65(d，1H)，3.32-3.42(m，5H)，1.82-1.92(m，1H)，1.39-1.65(m，5H)，1.44(s，9H)MS(m/z)：361(M+1)
Embodiment 5
1, N-benzyl-3-pyrrolidine oximes is synthetic
With N-benzyl-3-pyrrolidone (200g 1.14mol) is dissolved in the mixing solutions of 2.1L ethanol and 710mL water, add successively in the room temperature downhill reaction system sodium-acetate (279.6g, 3.41mol) and oxammonium hydrochloride (236g, 3.41mol), stirring is spent the night.TLC (volume percent of petrol ether/ethyl acetate=5: 1) shows that raw material disappears, and reaction is finished.Ethanol in the reaction solution is spun off, add 2.0L water and use ethyl acetate extraction twice, each 800mL.Organic phase is merged, and with the saturated common salt washing once, anhydrous sodium sulfate drying filters, and concentrates.Crude product petroleum ether twice, vacuum-drying obtains N-benzyl-3-pyrrolidine oximes (white solid, 187g, 86%).
1H?NMR：(400MHz，CDCl
3)δ7.22-7.33(m，5H)，3.33(s，2H)，2.52-2.58(t，2H)，2.45-2.49(t，2H)，2.43(s，2H)，2.24(br，1H)
MS(m/z)：191(M+1)
2, N-benzyl-3-nitro-pyrrole alkane is synthetic
With urea hydrogen peroxide (58.5g 0.622mol) is dissolved in the 415mL acetonitrile, and makes system reduce to 0 ℃, slowly drip then trifluoroacetic anhydride (120g, 0.571mol) and the mixed solution of 415mL acetonitrile.After dripping off, reaction system continues stirring down at 0 ℃ and obtained the trifluoro Peracetic Acid in 30 minutes.Meanwhile, with N-benzyl-3-pyrrolidine oximes (50g, 0.263mol), Sodium phosphate dibasic (205g, 1.46mol) and the mixture heating up to 80 of 830mL acetonitrile ℃, under this temperature, slowly drip the acetonitrile solution of firm ready-made trifluoro Peracetic Acid, drip off the back and continue to stir two hours.Reaction is cooled to room temperature, adds 2.0L water and 500mL 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 N-benzyl-3-nitro-pyrrole alkane (faint yellow solid, 37.4g, 69%) through the silicagel column purifying.
1H?NMR：(400MHz，CDCl
3)δ7.26-7.38(m，5H)，3.84-3.95(m，1H)，3.62(s，2H)，2.86-2.94(m，2H)，2.66-2.74(m，2H)，2.01-2.41(m，4H)
MS(m/z)：208(M+1)
3, N-benzyl-3-propionic aldehyde base-3-nitro-pyrrole alkane is synthetic
With N-benzyl-3-nitro-pyrrole alkane (20g, 97.0mmol) and triethylamine (0.98g 9.7mmol) is dissolved in the 60mL acetonitrile, and (8.69g, 154mmol) and the mixed solution of 10mL acetonitrile, stirring is spent the night to drip propenal under the room temperature.TLC (volume percent of petrol ether/ethyl acetate=1: 1) shows that raw material disappears, and reaction is finished.Concentrate, crude product gets N-benzyl-3-propionic aldehyde base-3-nitro-pyrrole alkane (yellow oily, 19.8g, 78%) through the silicagel column purifying.
1H?NMR：(400MHz，CDCl
3)δ9.62-9.68(t，1H)，7.26-7.38(m，5H)，3.65(s，2H)，2.90-2.94(d，2H)，2.64-2.68(d，2H)，2.38-2.42(m，2H)，2.16-2.30(m，5H)，1.95-2.03(m，1H)
MS(m/z)：263(M+1)
4,1,7-diaza spiro [4,5] nonane synthetic
(12g 46mmol) is blended in the methyl alcohol with 2.0 Cray Buddhist nun (Raney) Ni, and in room temperature, hydrogen pressure 20Psi stirs and spends the night with N-benzyl-3-propionic aldehyde base-3-nitro-pyrrole alkane.TLC (volume percent of petrol ether/ethyl acetate=1: 1) shows that raw material disappears, and reaction finishes.The reaction solution diatomite filtration, filtrate concentrating obtains 1,7-diaza spiro [4,5] nonane (yellow oily, 8.95g, 90%)
1H?NMR：(400MHz，CDCl
3)δ7.24-7.32(m，5H)，3.59(s，2H)，3.02(br，1H)，2.70-2.80(m，2H)，2.40-2.44(d，1H)，2.20-2.30(m，3H)，1.39-1.75(m，6H)MS(m/z)：217(M+1)。
Claims (10)
1.7-the synthetic method of diaza spiro [4,5] nonane and derivative thereof is characterized in that, is raw material with the pyrrolidone of amido protecting group, is dissolved in the second alcohol and water, successively adds basic cpd, oxammonium hydrochloride, obtains the pyrrolidine oximes of amido protecting group; The pyrrolidine oximes of amido protecting group in Sodium phosphate dibasic and acetonitrile, the oxidized dose of 3-nitro-pyrroles who is oxidized to the amido protecting group; 3-nitro-the pyrroles of amido protecting group gets the 3-propionic aldehyde base-3-nitro-pyrrole alkane of amido protecting group through your addition of Mike; The 3-propionic aldehyde base of amido protecting group-3-nitro-pyrrole alkane is in organic solvent; add catalyzer, hydrogenation obtains target product 1,7-diaza spiro [4; 5] nonane; 1, the further derivatize of 7-diaza spiro [4,5] nonane; be that acylations or alkylated reaction obtain 1; 7-diaza spiro [4,5] nonane derivatives, reaction formula is as follows:
Wherein, PG
1And PG
2Be the substituting group on the nitrogen-atoms, a kind of in hydrogen atom, tertbutyloxycarbonyl, carbobenzoxy-(Cbz) or the benzyl, PG
1With PG
2Identical or different.
2. according to claim 11; 7-diaza spiro [4; 5] synthetic method of nonane and derivative thereof; it is characterized in that; in becoming the oxime reaction process; the basic cpd that is adopted is a kind of in salt of wormwood, yellow soda ash, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium phosphate, sodium-acetate or the Potassium ethanoate; the basic cpd consumption is 2～8 times of equivalents of the pyrrolidone of amido protecting group; the consumption of oxammonium hydrochloride is 2～8 times of equivalents of the pyrrolidone of amido protecting group, and the temperature when adding basic cpd is-20～30 ℃.
3. according to claim 21; 7-diaza spiro [4; 5] synthetic method of nonane and derivative thereof; it is characterized in that; the basic cpd consumption is 3～5 times of equivalents of the pyrrolidone of amido protecting group; the consumption of oxammonium hydrochloride is 3～5 times of equivalents of the pyrrolidone of amido protecting group, and the temperature that adds basic cpd is 10～30 ℃.
4. according to claim 11; 7-diaza spiro [4; 5] synthetic method of nonane and derivative thereof; it is characterized in that; in oxidation reaction process; oxygenant is a kind of in trifluoro Peracetic Acid, Peracetic Acid, metachloroperbenzoic acid, urea hydrogen peroxide or the potassium hydrogen persulfate, and the oxygenant consumption is 1～5 times of equivalent of the pyrrolidine oximes of amido protecting group, and temperature of reaction is 50～100 ℃.
5. according to claim 41, the synthetic method of 7-diaza spiro [4,5] nonane and derivative thereof is characterized in that, the oxygenant consumption is 2～4 times of equivalents of the pyrrolidine oximes of amido protecting group, and temperature of reaction is 70～90 ℃.
6. according to claim 11, the synthetic method of 7-diaza spiro [4,5] nonane and derivative thereof is characterized in that, in the reversal of the Michael addition process, the consumption of propenal is 1～3 times of equivalent of the 3-nitro-pyrroles of amido protecting group; The consumption of triethylamine is 0.1～1 times of equivalent of derivative that has the 3-nitro-pyrroles of amido protecting group.
7. according to claim 61, the synthetic method of 7-diaza spiro [4,5] nonane and derivative thereof is characterized in that, the consumption of propenal is 1.5～2 times of equivalents of the 3-nitro-pyrroles of amido protecting group; The consumption of triethylamine is 0.1～0.4 times of equivalent of derivative that has the 3-nitro-pyrroles of amido protecting group.
8. according to claim 11,7-diaza spiro [4,5] synthetic method of nonane and derivative thereof, it is characterized in that in reduction ring closure reaction process, organic solvent is selected methyl alcohol, ethanol, Virahol for use, a kind of in ethyl acetate or the tetrahydrofuran (THF), catalyzer is a kind of in Raney's nickel, palladium charcoal or the platinum dioxide, the catalyst levels mass percent be the amido protecting group 3-propionic aldehyde base-3-nitro-pyrrole alkane 5～20%, reaction pressure is 30～60psi; Temperature of reaction is 40～65 ℃.
9. according to claim 81, the synthetic method of 7-diaza spiro [4,5] nonane and derivative thereof is characterized in that, the catalyst levels mass percent be the amido protecting group 3-propionic aldehyde base-3-nitro-pyrrole alkane 8～16%, reaction pressure is 45～50psi; Temperature of reaction is 45～55 ℃.
10. according to claim 11, the synthetic method of 7-diaza spiro [4,5] nonane and derivative thereof is characterized in that, to 1, in the process of the further derivatize of 7-diaza spiro [4,5] nonane, acyl chlorides, alkylating reagent, the consumption of acid anhydrides is 1,1～3 times of equivalent of 7-diaza spiro [4,5] nonane.
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| CN106939001A (en) * | 2017-02-07 | 2017-07-11 | 武汉药明康德新药开发有限公司 | A kind of synthetic method of the dicarboxylic acids of 5 benzyl, 2 tert-butyl group, 8 oxygen, 2,5 diaza spiro [3,5] nonyl 2,5 |
| CN107383026A (en) * | 2017-06-29 | 2017-11-24 | 武汉药明康德新药开发有限公司 | A kind of synthetic method of the t-butyl formate of 7 methylol 2,5 diaza spiro [3,4] octane 2 |
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| CN112321599A (en) * | 2020-11-25 | 2021-02-05 | 合肥远志医药科技开发有限公司 | Synthesis method of drug intermediate 7-oxo-2-azaspiro [3.5] nonane |
| CN113527141A (en) * | 2021-07-08 | 2021-10-22 | 江西省科学院应用化学研究所 | Synthetic method of spiro [2,5] octane derivative |
| CN113527141B (en) * | 2021-07-08 | 2023-04-14 | 江西省科学院应用化学研究所 | Synthetic method of spiro [2,5] octane derivative |
| CN113717180A (en) * | 2021-10-15 | 2021-11-30 | 安徽大学 | Synthesis method of 2-Boc-2, 7-diaza-spiro [4,4] nonane |
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