CN102659678B - Method for synthesis of 1-carbonyl-7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester - Google Patents
Method for synthesis of 1-carbonyl-7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester Download PDFInfo
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- CN102659678B CN102659678B CN201210098939.7A CN201210098939A CN102659678B CN 102659678 B CN102659678 B CN 102659678B CN 201210098939 A CN201210098939 A CN 201210098939A CN 102659678 B CN102659678 B CN 102659678B
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Abstract
The invention relates to a field of drug intermediate synthesis and especially relates to a method for synthesis of 1-carbonyl-7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester. The method is characterized in that a compound II and a compound V as raw materials undergo a reaction to produce a compound VI; and the compound VI undergoes an epoxidation reaction and a ring-enlargement reaction to produce a compound I. The method has the advantages of less reaction processes, simple operation, cheap and easily available raw materials, high yield and high total yield of 70.7%, and is suitable for large scale preparation.
Description
Technical field
The present invention relates to the synthetic field of pharmaceutical intermediate, be specifically related to the synthetic method of 1-carbonyl-7-azaspiro [3.5] nonane-7-carboxylic acid-tert-butyl ester.
Background technology
It is main skeleton (Bioorganic & Medicinal Chemistry Letters that a kind of Novel spiral inhibitors of fatty acid amide hydrolase of recent findings be take 7-azaspiro [3.5] nonane and 1-carbonyl-8-azaspiro [4.5] decane, 21 (21), 6538-6544; 2011).
US2005/0070609 A1 has reported take 1-carbonyl-7-azaspiro [3.5] nonane-7-carboxylic acid-tert-butyl ester as the synthetic a series of derivatives of raw material, these compounds can regulate and control the activity of Chemokine Receptors CCR3 and CCR5, therefore this compounds and pharmacy acceptable salt thereof can be used for the prevention disease relevant to Chemokine Receptors with treatment, for example HIV virus infection and acquired immune deficiency syndrome (AIDS).This compounds helps delay in addition in addition, treatment, or prevent the diseases such as some inflammation and immunomodulatory obstacle.
1-carbonyl-7-azaspiro [3.5] nonane-7-carboxylic acid-tert-butyl ester (I) will be a kind of medicine intermediate that has very much market potential, take that it can design the derivative novel and diversified with composite structure as molecular skeleton, for screening and the research and development of the innovation medicine for different target spots.
US2005/0070609 A1 has reported the synthetic method of a kind of 1-carbonyl-7-azaspiro [3.5] nonane-7-carboxylic acid-tert-butyl ester:
Reagent and condition: (a) two (TMS) potassium amide (KHMDS), tetrahydrofuran (THF) (THF); (b) LiBF
4, toluene, yield: 78%.
III is expensive for this invention starting raw material, is difficult to buy a large amount of products on market.In synthesis material III, need to use Nitromethane 99Min., this reagent is inflammable and explosive, is not suitable for scale operation.
Summary of the invention
The object of this invention is to provide a kind of efficient, synthetic method of possessing 1-carbonyl-7-azaspiro [3.5] nonane-7-carboxylic acid-tert-butyl ester that extensive preparation is worth.Mainly solve that existing 1-carbonyl-7-azaspiro [3.5] nonane-7-carboxylic acid-tert-butyl ester yield is low, raw materials cost is expensive, cannot scale operation etc. technical problem.
It is raw material that preparation method of the present invention be take Compound I I and compound V, and reaction obtains compound VI; Through epoxidation and ring expansion, obtain 1-carbonyl-7-azaspiro [3.5] nonane-7-carboxylic acid-tert-butyl ester (I) again.Reaction formula is as follows:
Compound I I in the first step reaction wherein: compound V: NaH three's mol ratio preferably 1.0: 1.0: 1.5～4.0.
When the first step reaction prepares compound VI by Compound I I and compound V, the preferred tetrahydrofuran (THF) of reaction solvent or DMF.
Preferably 60 ℃～120 ℃ of the first step reaction response temperature.
Second step reaction prepares Compound I by compound VI, wherein the preferred metachloroperbenzoic acid of superoxide (mCPBA) or hydrogen peroxide.
The mol ratio preferably 1.0: 1.0～1.0: 1.5 of compound VI and superoxide in second step reaction.
In second step reaction, the preferred methylene dichloride of reaction solvent (DCM) or acetonitrile.
At room temperature, preferred temperature of reaction is 10 ℃～60 ℃ in second step reaction.
Preparation method's reactions steps of the present invention is few, simple to operate, and raw material is cheaply easy to get, and productive rate is high, and total recovery can reach 70.7%, and is applicable to extensive preparation.
Embodiment
Embodiment 1
Synthesizing of compound VI:
Compound V (1370g, 2.94mol, 1.0eq.) adds in 6L THF, adds NaH (282g, 7.05mol, 2.4eq.), back flow reaction 3h, then add Compound I I (585g, 2.94mol, 1.0eq.), backflow 8h, reacts completely.Be spin-dried for, with ether, carry out recrystallization, obtain compound VI light yellow solid 658.5g, directly next step reaction.
Synthesizing of Compound I:
Compound VI (658.5.0g, 2.94mol, 1.0eq.) adds in 7LDCM, and ice bath to 0 ℃ adds mCPBA (80%) (634.2g, 2.94mol, 1.0eq.), and stirred overnight at room temperature, reacts completely.Use NaOH solution washing, anhydrous Na
2sO
4dry, be spin-dried for.With ethyl acetate (EA) recrystallization, obtain Compound I white solid 500g, two step yields 70.7%, purity: 99%.
1H?NMR(400MHz，CDCl3)δ(ppm)1.47(s，9H)，1.52(s，2H)，1.63-1.92(m，4H)，3.02-3.07(t，2H)，3.37-3.44(m，2H)，3.55-3.61(m，2H)。
Embodiment 2
Synthesizing of Compound I:
Compound VI (65.85g, 0.294mol, 1.0eq.) adds in 700mL acetonitrile, ice bath to 0 ℃, add hydrogen peroxide (85%) (17.5g, 0.441mol, 1.5eq.), 50 ℃ of stirrings are spent the night, react completely, add S-WAT cancellation reaction, after concentrating.After adding EA 500mL to dissolve, use salt water washing, anhydrous sodium sulfate drying, concentrated, then obtain Compound I white solid 55g, yield 83.5% with EA recrystallization.
1H?NMR(400MHz，CDCl3)δ(ppm)1.47(s，9H)，1.52(s，2H)，1.63-1.92(m，4H)，3.02-3.07(t，2H)，3.37-3.44(m，2H)，3.55-3.61(m，2H)。
Claims (4)
1. a preparation method for compound (I), comprising:
While wherein preparing compound VI by Compound I I and compound V, Compound I I: compound V: NaH three's mol ratio is 1.0: 1.0: 1.5～4.0, temperature of reaction is 60 ℃～120 ℃; Wherein superoxide is metachloroperbenzoic acid or hydrogen peroxide.
2. the preparation method of claim 1, while wherein preparing compound VI by Compound I I and compound V, reaction solvent is tetrahydrofuran (THF) or DMF.
3. the preparation method of claim 1, while wherein preparing Compound I by compound VI, the mol ratio of compound VI and superoxide is 1.0: 1.0～1.0: 1.5.
4. the preparation method of claim 1, while wherein preparing Compound I by compound VI, the preferred methylene dichloride of reaction solvent or acetonitrile.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210098939.7A CN102659678B (en) | 2012-03-31 | 2012-03-31 | Method for synthesis of 1-carbonyl-7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester |
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| CN201210098939.7A CN102659678B (en) | 2012-03-31 | 2012-03-31 | Method for synthesis of 1-carbonyl-7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester |
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| CN102659678A CN102659678A (en) | 2012-09-12 |
| CN102659678B true CN102659678B (en) | 2014-10-22 |
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| CN201210098939.7A Active CN102659678B (en) | 2012-03-31 | 2012-03-31 | Method for synthesis of 1-carbonyl-7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester |
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Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US7091211B2 (en) * | 2003-07-31 | 2006-08-15 | Merck & Co., Inc. | Cyclopentyl modulators of chemokine receptor activity |
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Non-Patent Citations (4)
| Title |
|---|
| A Novel and General Route to Diverse A-Ring Aromatic Trichothecanes via Cyclobutanes;Hideo Nemoto et al.;《Tetrahedron》;19961231;第52卷(第31期);第10363-10374页 * |
| E. E. SCHWEIZER et al..Reactions of Phosphorus Compounds. XIII. Preparations and Reactions of Cyclopropyltriphenylphosphonium Bromide.《The Journal of Organic Chemistry》.1968,第33卷(第1期),第336-339页. |
| Hideo Nemoto et al..A Novel and General Route to Diverse A-Ring Aromatic Trichothecanes via Cyclobutanes.《Tetrahedron》.1996,第52卷(第31期),第10363-10374页. |
| Reactions of Phosphorus Compounds. XIII. Preparations and Reactions of Cyclopropyltriphenylphosphonium Bromide;E. E. SCHWEIZER et al.;《The Journal of Organic Chemistry》;19680131;第33卷(第1期);第336-339页 * |
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Effective date of registration: 20160314 Address after: 210000, Jiangsu, Nanjing hi tech Development Zone, 10 Spark Road, ding industry, 100 Thai biological building C block 11 building Patentee after: NANJING FURUN KAIDE BIOLOGICAL PHARMACEUTICAL CO., LTD. Address before: 210061 Nanjing high tech Industrial Development Zone, Jiangsu Province Road, No. 10 Patentee before: Nanjing Medical Stone and Medicine Research and Development Co., Ltd. |