CN105503891A - 5-tert-butyloxycarbonyl-2-oxa-5-azabicyclo[2.2.1]heptane-1-carboxylic acid synthesis method - Google Patents
5-tert-butyloxycarbonyl-2-oxa-5-azabicyclo[2.2.1]heptane-1-carboxylic acid synthesis method Download PDFInfo
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Abstract
The present invention relates to a 5-tert-butyloxycarbonyl-2-oxa-5-azabicyclo[2.2.1]heptane-1-carboxylic acid synthesis method. In the prior art, the suitable industrial synthesis method does not exist. A purpose of the present invention is mainly to solve the technical problem in the prior art. The synthesis method comprises six steps, and specifically comprises that a compound 1 and Boc anhydride react under an alkaline condition to obtain a compound 2, the compound 2 is oxidized into a compound 3 by using a 2,2,6,6-tetramethyl piperidine oxide, the compound 3 reacts with a Grignard reagent to obtain a compound 4, the carboxylic acid 4 is reduced with lithium aluminum hydride to obtain a compound 5, the compound 5 reacts with n-butyl lithium and p-tosyl chloride in two stages to obtain a compound 6, and the compound 6 is oxidized with sodium periodate to obtain a final compound 7. The reaction formula is defined in the specification.
Description
Technical field
The synthetic method of compound 5-tertbutyloxycarbonyl-2-oxa--5-azabicyclic [2.2.1] heptane-1-carboxylic acid that the present invention relates to.
Background technology
Compound 5-tertbutyloxycarbonyl-2-oxa--5-azabicyclic [2.2.1] heptane-1-carboxylic acid (CAS:1330763-18-2) and relevant derivative have widespread use in pharmaceutical chemistry and organic synthesis.Current 5-tertbutyloxycarbonyl-2-oxa--5-azabicyclic [2.2.1] though this material of heptane-1-carboxylic acid has report, but does not find applicable industrialized synthetic method.Therefore, need exploitation raw material to be easy to get, easy to operate, reaction is easy to control, and overall yield is applicable to, and is applicable to the synthetic method of suitability for industrialized production.
Summary of the invention
The object of the invention is exploitation one to have raw material and be easy to get, easy to operate, reaction is easy to control, the synthetic method of 5-tertbutyloxycarbonyl-2-oxa--5-azabicyclic [2.2.1] heptane-1-carboxylic acid that yield is higher.Mainly solve the technical problem not being applicable to Industrialized synthesis method at present.
Technical scheme of the present invention: the synthetic method of 5-tertbutyloxycarbonyl-2-oxa--5-azabicyclic [2.2.1] heptane-1-carboxylic acid, the present invention divides six steps, first by compound
1react in sodium hydroxide solution with Boc acid anhydrides, obtain compound
2, then use 2,2,6,6-tetramethyl piperidine oxides to generate compound
3, then compound
3compound is obtained with form reagent react
4, obtain compound with tetrahydrochysene lithium aluminium reducing carboxylic acid 4
5, compound
5two stages and n-Butyl Lithium and Tosyl chloride are divided to be obtained by reacting compound
6, final compound
6add sodium periodate and ruthenium trichloride, oxidation obtains finalization compound
7.
The Chinese lexical or textual analysis of the present invention's abbreviation: TLC: tlc; R
f: Rf value; TEMPO:2,2,6,6-tetramethyl piperidine oxide compound.
In above-mentioned reaction, solvent is the one in tetrahydrofuran (THF), ethyl acetate, methyl alcohol, tetracol phenixin, methylene dichloride, water, acetonitrile.The first step temperature of reaction room temperature, tetrahydrofuran (THF) makes solvent; Second step temperature of reaction room temperature, methylene dichloride makes solvent; Third and fourth, five step temperature of reaction 0 DEG C, tetrahydrofuran (THF) makes solvent; Six-step process temperature room temperature, acetonitrile as solvents.
Beneficial effect of the present invention: reaction process of the present invention is reasonable in design; which employs be easy to get, can the raw material 4-hydroxyl pyrrolidine-2-carboxylic acid of large-scale production; by the method for six step synthesis 5-tertiary butyl oxycarbonyl-2-oxa--5-azabicyclic [2.2.1] heptane-1-carboxylic acids; the method route is short; yield can up to 11.4%; reaction is easy to amplify, easy to operate.
Embodiment
Reaction formula of the present invention is as follows:
Embodiment 1:
By compound
1(50g, 0.382mol) is dissolved in tetrahydrofuran (THF) (500mL), and then 0 degree Celsius drips aqueous sodium hydroxide solution (33.6g, 0.84mol, 1M), then drip BOC acid anhydrides (82.4g, 0.382mol). dropwise, stirred overnight at room temperature.TLC (methylene chloride/methanol volume ratio=10/1, R
f=0.3) display reaction is complete.Reaction solution concentrates, and removing tetrahydrofuran (THF), is then acidified to pH=2 with 1N hydrochloric acid soln.Aqueous phase dichloromethane extraction several, organic phase drying is spin-dried for, and obtains compound
2(66.3g), yield: 71%.
By compound
2(110g, 0.476mol) is dissolved in methylene dichloride (2.0L), adds trichloroisocyanuric acid (110g while stirring, 0.476mol), and then add 2,2,6,6-tetramethyl piperidine oxide compound (3.7g, 0.0238mol), room temperature reaction 1h, then goes out with shrend, filters out insolubles, aqueous phase dichloromethane extraction several, merge organic phase, dry and vacuum concentration is extremely done, and obtains compound
3(78g), yield 72%.
By compound
3(78g, 0.34mol) is dissolved in anhydrous tetrahydro furan (1.0L), drips the tetrahydrofuran solution of vinyl magnesium bromide (954mL, 0.954mol, 1M) while stirring.Dropwise, under nitrogen protection 0
oc reacts 30min, TLC (methylene chloride/methanol volume ratio=10/1, R
f=0.3) display reaction is complete, and saturated aqueous ammonium chloride cancellation is reacted, and then vacuum concentration falls most of tetrahydrofuran (THF), then use 1N salt acid for adjusting pH to 3 ~ 4, aqueous phase dichloromethane extraction several, merges organic phase, anhydrous sodium sulfate drying, vacuum concentration obtains crude Compound to dry
4(65g), yield 74%, is not further purified, and directly throws next step.
Crude Compound
4(65g, 0.253mol) is dissolved in anhydrous tetrahydro furan (200mL), and then 0
oc adds tetrahydrochysene lithium aluminium (11.5g, 0.304mol) in batches, then room temperature reaction 1h.TLC (methylene chloride/methanol volume ratio=10/1, R
f=0.8) display reaction is complete, then priority H
2o (11.5mL), the aqueous sodium hydroxide solution (11.5mL) of mass percentage 15% and H
2o (36mL) cancellation is reacted, and stirring at room temperature 20min, then filters, filter cake washed with dichloromethane several, and filtrate anhydrous sodium sulfate drying, then vacuum concentration is to dry.The crude product silica gel chromatography (petrol ether/ethyl acetate volume ratio=10/1 ~ 5/1) of oily obtains pure compound 5 (16.5g), yield 27%.
Compound 5 (12g, 0.049mol) is dissolved in anhydrous tetrahydro furan (200mL), then under nitrogen protection, 0
oc drips n-Butyl Lithium (19.7mL, 0.049mol).Dropwise, stir 30min, then add Tosyl chloride (9.3g, 0.049mol) in batches, 0
oc reacts 1h, and then drips n-Butyl Lithium (19.7mL, 0.049mol).1h is stirred, TLC (methylene chloride/methanol volume ratio=20/1, R at same temperature
f=0.8) display reaction is complete.Reaction uses saturated aqueous ammonium chloride cancellation, extraction into ethyl acetate.Merge organic phase, dry, then vacuum concentration is to dry.Gained crude product silica gel chromatography (petrol ether/ethyl acetate volume ratio=50/1 ~ 20/1) obtains pure compound 6 (8.0g), yield 73%.
By compound 6 (4.5g, 0.02mol) be dissolved in acetonitrile (50mL), then tetracol phenixin/water (50mL/83mL) is added under room temperature condition respectively, sodium bicarbonate (9.07g, 0.108mol), and stir 15min, and then add sodium periodate (37.3g respectively, 0.1744mol), ruthenium trichloride (0.67g, 0.0032mol).Reaction stirring is spent the night.TLC (petrol ether/ethyl acetate volume ratio=4/1, R
f=0) display reaction is complete.Reacting liquid filtering, filtrate isolates organic phase.Aqueous phase 1N salt acid for adjusting pH value to 4 ~ 5, and with dichloromethane extraction for several times, merging machine phase, with anhydrous sodium sulfate drying, vacuum concentration obtains compound 7 (4.0g), yield 82% to dry.
1MeOD，δ4.566-4.564(s,1H),3.984-3.962(q,1H),3.913-3.903(br,1H),3.671-3.646(d,1H),3.457-3.435(d,1H),2.208-2.158(t,1H),2.092-2.067(d,1H),1.470(s,9H)。
Embodiment 2:
By compound
1(200g, 1.53mol) is dissolved in tetrahydrofuran (THF) (1.5L), and then 0 degree Celsius drips aqueous sodium hydroxide solution (128.5g, 3.21mol, 1M), BOC acid anhydrides (400.7g, 1.84mol). dropwise, stirred overnight at room temperature.TLC (methylene chloride/methanol volume ratio=10/1, R
f=0.3) display reaction is complete.Reaction solution concentrates, and removing tetrahydrofuran (THF), is then acidified to PH=2 with 1N hydrochloric acid soln.Aqueous phase dichloromethane extraction several, organic phase drying is spin-dried for, and obtains compound
2(237.8g), yield: 67.2%.
By compound
2(178g, 0.77mol) is dissolved in methylene dichloride (2.0L), adds trichloroisocyanuric acid (178.89g while stirring, 0.77mol), and then add 2,2,6,6-tetramethyl piperidine oxide compound (6.05g, 0.0385mol), room temperature reaction 1h, then goes out with shrend, filters out insolubles, aqueous phase dichloromethane extraction several, merge organic phase, dry and vacuum concentration is extremely done, and obtains compound
3(180g), yield 100%.
By compound
3(100g, 0.436mol) is dissolved in anhydrous tetrahydro furan (1.5L), drips the tetrahydrofuran solution of vinyl magnesium bromide (1.09L, 1.09mol, 1M) while stirring.Dropwise, under nitrogen protection 0
oc reacts 30min, TLC (methylene chloride/methanol volume ratio=10/1, R
f=0.3) display reaction is complete, and saturated aqueous ammonium chloride cancellation is reacted, and then vacuum concentration falls most of tetrahydrofuran (THF), then use 1N salt acid for adjusting pH to 3 ~ 4, aqueous phase dichloromethane extraction several, merges organic phase, anhydrous sodium sulfate drying, vacuum concentration obtains crude Compound to dry
4(112.2g), yield 79.3%, is not further purified, and directly throws next step.
Crude Compound
4(113g, 0.44mol) is dissolved in anhydrous tetrahydro furan (1.5L), and then 0
oc adds tetrahydrochysene lithium aluminium (20g, 0.527mol) in batches, then room temperature reaction 1h.TLC (methylene chloride/methanol volume ratio=10/1, R
f=0.8) display reaction is complete, then priority use water (20mL), the aqueous sodium hydroxide solution (20mL) of 15% and water (60mL) cancellation reaction, stirring at room temperature 20min, then filter, filter cake washed with dichloromethane several, filtrate anhydrous sodium sulfate drying, then vacuum concentration is to dry.The crude product silica gel chromatography (petrol ether/ethyl acetate volume ratio=10/1 ~ 5/1) of oily obtains pure compound 5 (41.5g), yield 38.8%.
Compound 5 (55g, 0.226mol) is dissolved in anhydrous tetrahydro furan (1.5L), then under nitrogen protection, 0
oc drips n-Butyl Lithium (90.4mL, 0.226mol, 2.5M).Dropwise, stir 30min, then add Tosyl chloride (43.1g, 0.226mol) in batches, 0
oc reacts 1h, and then drips n-Butyl Lithium (90.4mL, 0.226mol, 2.5M).1h is stirred, TLC (methylene chloride/methanol volume ratio=20/1, R at same temperature
f=0.8) display reaction is complete.Reaction uses saturated aqueous ammonium chloride cancellation, extraction into ethyl acetate.Merge organic phase, dry, then vacuum concentration is to dry.Gained crude product silica gel chromatography (petrol ether/ethyl acetate volume ratio=50/1 ~ 20/1) obtains pure compound
6(33.3g), yield 65.4%.
By compound
6(28g, 0.124mol) be dissolved in acetonitrile (400mL), then tetracol phenixin/water (400mL/340mL) is added under room temperature condition respectively, sodium bicarbonate (56.4g, 0.671mol), and stir 15min, and then add sodium periodate (231.3g respectively, 1.08mol), ruthenium trichloride (4.12g, 0.02mol).Reaction stirring is spent the night.TLC (petrol ether/ethyl acetate volume ratio=4/1, R
f=0) display reaction is complete.Reacting liquid filtering, mother liquor isolates organic phase.Aqueous phase 1N salt acid for adjusting pH value to 4 ~ 5, and with dichloromethane extraction for several times, merging machine phase, with anhydrous sodium sulfate drying, vacuum concentration obtains compound 7 (25.7g), yield 85% to dry.
1MeOD，δ4.566-4.564(s,1H),3.984-3.962(q,1H),3.913-3.903(br,1H),3.671-3.646(d,1H),3.457-3.435(d,1H),2.208-2.158(t,1H),2.092-2.067(d,1H),1.470(s,9H)。
Claims (7)
1. a synthetic method for 5-tertbutyloxycarbonyl-2-oxa--5-azabicyclic [2.2.1] heptane-1-carboxylic acid, is characterized in that comprising the following steps: the first step reaction is by compound
1react under sodium hydroxide solution condition with Boc acid anhydrides, obtain compound
2, second step reaction 2,2,6,6-tetramethyl piperidine oxides generates compound
3, three-step reaction compound
3compound is obtained with form reagent react
4, four-step reaction tetrahydrochysene lithium aluminium reducing carboxylic acid 4 obtains compound
5, the 5th step compound of reaction
5two stages and n-Butyl Lithium and Tosyl chloride are divided to be obtained by reacting compound
6, six-step process compound
6add sodium periodate and ruthenium trichloride, oxidation obtains finalization compound
7, reaction formula is as follows:
。
2. the synthetic method of a kind of 5-tertbutyloxycarbonyl-2-oxa--5-azabicyclic [2.2.1] heptane-1-carboxylic acid according to claim 1, is characterized in that: the first step temperature of reaction room temperature, tetrahydrofuran (THF) makes solvent.
3. the synthetic method of a kind of 5-tertbutyloxycarbonyl-2-oxa--5-azabicyclic [2.2.1] heptane-1-carboxylic acid according to claim 1, is characterized in that: second step temperature of reaction room temperature, methylene dichloride makes solvent.
4. the synthetic method of a kind of 5-tertbutyloxycarbonyl-2-oxa--5-azabicyclic [2.2.1] heptane-1-carboxylic acid according to claim 1, is characterized in that: three-step reaction temperature 0 DEG C, tetrahydrofuran (THF) makes solvent.
5. the synthetic method of a kind of 5-tertbutyloxycarbonyl-2-oxa--5-azabicyclic [2.2.1] heptane-1-carboxylic acid according to claim 1, is characterized in that: four-step reaction temperature 0 DEG C, tetrahydrofuran (THF) makes solvent.
6. the synthetic method of a kind of 5-tertbutyloxycarbonyl-2-oxa--5-azabicyclic [2.2.1] heptane-1-carboxylic acid according to claim 1, it is characterized in that, the 5th step temperature of reaction 0 DEG C, tetrahydrofuran (THF) makes solvent.
7. the synthetic method of a kind of 5-tertbutyloxycarbonyl-2-oxa--5-azabicyclic [2.2.1] heptane-1-carboxylic acid according to claim 1, is characterized in that, six-step process temperature room temperature, acetonitrile as solvents.
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| CN201410488805.5A CN105503891B (en) | 2014-09-23 | 2014-09-23 | A kind of synthetic method of the carboxylic acid of 5 tertbutyloxycarbonyl, 2 oxa-, 5 azabicyclic [2.2.1] heptane 1 |
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| CN201410488805.5A CN105503891B (en) | 2014-09-23 | 2014-09-23 | A kind of synthetic method of the carboxylic acid of 5 tertbutyloxycarbonyl, 2 oxa-, 5 azabicyclic [2.2.1] heptane 1 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1986548A (en) * | 2005-12-22 | 2007-06-27 | 上海药明康德新药开发有限公司 | Industrial continuous preparing process of N-tert-butoxy carbonyl-5-aza-2-oxa-3-one-dicyclo-[2,2,1] heptane |
| WO2014009295A1 (en) * | 2012-07-13 | 2014-01-16 | Ucb Pharma S.A. | Imidazopyridine derivatives as modulators of tnf activity |
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2014
- 2014-09-23 CN CN201410488805.5A patent/CN105503891B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1986548A (en) * | 2005-12-22 | 2007-06-27 | 上海药明康德新药开发有限公司 | Industrial continuous preparing process of N-tert-butoxy carbonyl-5-aza-2-oxa-3-one-dicyclo-[2,2,1] heptane |
| WO2014009295A1 (en) * | 2012-07-13 | 2014-01-16 | Ucb Pharma S.A. | Imidazopyridine derivatives as modulators of tnf activity |
Non-Patent Citations (6)
| Title |
|---|
| CHAD A. VAN HUIS等: "Exploration of 4,4-disubstituted pyrrolidine-1,2-dicarboxamides as potent,orally active Factor Xa inhibitors with extended duration of action", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
| DAISUKE URABE等: "Application of r-Alkoxy Bridgehead Radical for Coupling of Oxygenated Carbocycles", 《ORGANIC LETTERS》 * |
| DONG-FENG ZHANG等，: "An improved synthesis of (lS,4S)-2-oxa-5-azabicyclo[2.2.1]heptane", 《CHINESE CHEMICAL LETTERS》 * |
| JOHN KRAPCHO，等: "Angiotensin-Converting Enzyme Inhibitors. Mercaptan, Carboxyalkyl Dipeptide,and Phosphinic Acid Inhibitors Incorporating 4-Substituted Prolines", 《J. MED. CHEM.》 * |
| LOUIS D. QUIN等: "Synthesis of Hexahydrophosphindole Oxides with Oxygen Functions at C-6", 《J. ORG. CHEM.》 * |
| S. RICHARD BAKER, MANUEL CASES等: "Synthesis of pyridine fused polycyclic amines using sequential ring-closing metathesis and radical cyclisation reactions", 《TETRAHEDRON LETTERS》 * |
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