CN105503891B - A kind of synthetic method of the carboxylic acid of 5 tertbutyloxycarbonyl, 2 oxa-, 5 azabicyclic [2.2.1] heptane 1 - Google Patents
A kind of synthetic method of the carboxylic acid of 5 tertbutyloxycarbonyl, 2 oxa-, 5 azabicyclic [2.2.1] heptane 1 Download PDFInfo
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- CN105503891B CN105503891B CN201410488805.5A CN201410488805A CN105503891B CN 105503891 B CN105503891 B CN 105503891B CN 201410488805 A CN201410488805 A CN 201410488805A CN 105503891 B CN105503891 B CN 105503891B
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Abstract
The present invention relates to a kind of synthetic method of the carboxylic acid of 5 azabicyclic [2.2.1] heptane of 5 tertbutyloxycarbonyl, 2 oxa- 1, mainly solves the technical problem currently without suitable Industrialized synthesis method.Six steps of the present invention point, reacted in the basic conditions by compound 1 and Boc acid anhydrides first, compound 2 is obtained, then with 2,2,6, the oxidation of 6 tetramethyl piperidine oxides generates compound 3, and then compound 3 obtains compound 4 with form reagent reacting, and compound 5 is obtained with tetrahydrochysene lithium aluminium reducing carboxylic acid 4, compound 5 reacts to obtain compound 6 in two stages with n-BuLi and paratoluensulfonyl chloride, and final compound 6 obtains final compound 7 with sodium periodate oxidation.Reaction equation is as follows：
Description
Technical field
Compound 5- tertbutyloxycarbonyls -2- oxa- -5- azabicyclics [2.2.1] heptane -1- carboxylic acids of the present invention
Synthetic method.
Background technology
Compound 5- tertbutyloxycarbonyl -2- oxa- -5- azabicyclics [2.2.1] heptane -1- carboxylic acids (CAS：1330763-
18-2) and related derivative has extensive use in pharmaceutical chemistry and organic synthesis.5- tertbutyloxycarbonyls -2- oxygen at present
Miscellaneous -5- azabicyclics [2.2.1] are not found suitable for industrialized synthesis though this material of heptane -1- carboxylic acids has been reported that
Method.Therefore it is easy to get, it is necessary to develop a raw material, easy to operate, reaction is easily controllable, and overall yield is adapted to, and is adapted to industrialization
The synthetic method of production.
The content of the invention
The purpose of the present invention is that exploitation one kind is easy to get with raw material, easy to operate, reacts easily controllable, the higher 5- of yield
The synthetic method of tertbutyloxycarbonyl -2- oxa- -5- azabicyclics [2.2.1] heptane -1- carboxylic acids.Mainly solve currently without suitable
The technical problem of Industrialized synthesis method.
Technical scheme：The conjunction of 5- tertbutyloxycarbonyls -2- oxa- -5- azabicyclics [2.2.1] heptane -1- carboxylic acids
Into method, six steps of the present invention point, reacted first by compound 1 and Boc acid anhydrides in sodium hydroxide solution, obtain compound 2, so
Generation compound 3 is aoxidized with 2,2,6,6- tetramethyl piperidine oxides afterwards, then compound 3 obtains chemical combination with form reagent reacting
Thing 4, compound 5 is obtained with tetrahydrochysene lithium aluminium reducing carboxylic acid 4, compound 5 in two stages with n-BuLi and tolysulfonyl
Chlorine reacts to obtain compound 6, and final compound 6 adds sodium metaperiodate and ruthenium trichloride, and oxidation obtains final compound 7.
The Chinese lexical or textual analysis that the present invention abridges：TLC：Thin-layered chromatography；Rf：Rf value；TEMPO：2,2,6,6- tetramethyl piperazines
Pyridine oxide.
In above-mentioned reaction, solvent is in tetrahydrofuran, ethyl acetate, methanol, carbon tetrachloride, dichloromethane, water, acetonitrile
It is a kind of.First step reaction temperature room temperature, tetrahydrofuran make solvent；Second step reaction temperature room temperature, dichloromethane make solvent；The
3rd, 0 DEG C of four, five step reaction temperature, tetrahydrofuran makees solvent；Six-step process temperature room temperature, acetonitrile as solvents.
Beneficial effects of the present invention：Reaction process of the present invention is reasonable in design, which employs be easy to get, can large-scale production original
Expect 4- hydroxyl pyrrolidine -2- carboxylic acids, 5- tertiary butyl oxycarbonyls -2- oxa- -5- azabicyclics [2.2.1] heptan is synthesized by six steps
The method of alkane -1- carboxylic acids, this method route is short, and yield may be up to 11.4%, and reaction is easy to amplify, easy to operate.
Embodiment
Reaction equation of the present invention is as follows：
Embodiment 1：
Compound 1 (50 g, 0.382 mol) is dissolved in tetrahydrofuran (500 mL), then 0 degree Celsius of dropwise addition
Sodium hydrate aqueous solution (33.6 g, 0.84 mol, 1M), then BOC acid anhydrides (82.4 g, 0.382 mol) drops are added dropwise
Add complete, be stirred overnight at room temperature.TLC (methylene chloride/methanol volume ratios=10/1, Rf=0.3) display reaction finishes.Instead
Answer liquid to concentrate, remove tetrahydrofuran, be then acidified to pH=2 with 1N hydrochloric acid solutions.Aqueous phase dichloromethane extracted several times, have
Mutually drying is spin-dried for machine, obtains compound 2（66.3 g）, yield：71%.
Compound 2 (110g, 0.476 mol) is dissolved in dichloromethane (2.0 L）, trichlorine isocyanide urine is added while stirring
Acid (110 g, 0.476 mol）, then add 2,2,6,6- tetramethyl piperidine oxides (3.7 g, 0.0238 mol）, room
Temperature reaction 1h, is then quenched with water, and filters out insoluble matter, aqueous phase dichloromethane extracted several times, merges organic phase, dries and true
Sky is concentrated to dryness, and obtains (78 g of compound 3）, yield 72%.
By compound 3 (78 g, 0.34 mol）It is dissolved in anhydrous tetrahydro furan (1.0 L), second is added dropwise while stirring
The tetrahydrofuran solution of alkenyl magnesium bromide (954 mL, 0.954 mol, 1M).It is added dropwise, nitrogen protection lower 0oC reacts
30min, TLC (methylene chloride/methanol volume ratio=10/1, Rf=0.3) display reaction finishes, saturated aqueous ammonium chloride
Reaction is quenched, then is concentrated in vacuo most of tetrahydrofuran, then with 1N salt acid for adjusting pH to 3~4, aqueous phase dichloromethane
Alkane extracted several times, merge organic phase, anhydrous sodium sulfate drying, be concentrated in vacuo to and dry obtain crude Compound 4 (65 g), yield
74%, it is not further purified, directly throws in next step.
Crude Compound 4 (65 g, 0.253 mol) is dissolved in anhydrous tetrahydro furan (200 mL), and then 0oC points
Batch adds tetrahydrochysene lithium aluminium (11.5 g, 0.304 mol), then reacts at room temperature 1h.TLC (methylene chloride/methanol volume ratio=
10/1, Rf=0.8) display reaction finishes, and then successively uses H2O (11.5 mL), the hydroxide of weight/mass percentage composition 15%
Sodium water solution (11.5 mL) and H2Reaction is quenched in O (36 mL), and 20min is stirred at room temperature, then filters, filter cake dichloromethane
Alkane washs for several times, filtrate anhydrous sodium sulfate drying, is then concentrated in vacuo to dry.The crude product silica gel chromatography of oily
(petrol ether/ethyl acetate volume ratio=10/1 ~ 5/1) obtains pure compound 5 (16.5 g), yield 27%.
Compound 5 (12 g, 0.049 mol) is dissolved in anhydrous tetrahydro furan (200 mL), then in nitrogen
Under protection, 0oN-BuLi (19.7 mL, 0.049 mol) is added dropwise in C.It is added dropwise, stirs 30min, then addition pair in batches
Toluene sulfochloride (9.3 g, 0.049 mol), 0oC react 1h, be then added dropwise again n-BuLi (19.7 mL, 0.049
mol).1h, TLC (methylene chloride/methanol volume ratios=20/1, R are stirred at same temperaturef=0.8) display reaction finishes.
Reaction is quenched with saturated aqueous ammonium chloride, ethyl acetate extraction.Merge organic phase, dry, be then concentrated in vacuo to dry.Gained
Crude product obtains pure compound 6 with silica gel chromatography (petrol ether/ethyl acetate volume ratio=50/1 ~ 20/1)
(8.0 g), yield 73%.
Compound 6 (4.5 g, 0.02 mol) is dissolved in acetonitrile (50 mL), then under room temperature condition respectively
Carbon tetrachloride/water (50 mL/83 mL), sodium acid carbonate (9.07 g, 0.108 mol) are added, and stirs 15min, Ran Houzai
It is separately added into sodium metaperiodate (37.3 g, 0.1744 mol), ruthenium trichloride (0.67 g, 0.0032 mol).Reaction stirring
Overnight.TLC (petrol ether/ethyl acetate volume ratios=4/1, Rf=0) display reaction finishes.Reacting liquid filtering, filtrate point
Separate out organic phase.Aqueous phase with 1N salt acid for adjusting pH value to 4~5, and with dichloromethane extracted several times, merging machine phase, with nothing
Aqueous sodium persulfate is dried, and is concentrated in vacuo to and dry is obtained compound 7 (4.0 g), yield 82%.
1MeOD, δ 4.566-4.564 (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:
Compound 1 (200 g, 1.53 mol) is dissolved in tetrahydrofuran (1.5 L), then 0 degree Celsius of dropwise addition hydrogen
Aqueous solution of sodium oxide (128.5 g, 3.21 mol, 1M), BOC acid anhydrides (400.7 g, 1.84 mol) are added dropwise, room
Temperature is stirred overnight.TLC (methylene chloride/methanol volume ratios=10/1, Rf=0.3) display reaction finishes.Reaction solution concentrates,
Tetrahydrofuran is removed, is then acidified to PH=2 with 1N hydrochloric acid solutions.Aqueous phase dichloromethane extracted several times, organic phase are dried
It is spin-dried for, obtains compound 2 (237.8 g), yield：67.2%.
Compound 2 (178 g, 0.77 mol) is dissolved in dichloromethane (2.0 L), adds trichlorine isocyanide while stirring
Uric acid (178.89 g, 0.77 mol), then add 2,2,6,6- tetramethyl piperidine oxides (6.05 g, 0.0385
Mol), 1h is reacted at room temperature, is then quenched with water, insoluble matter is filtered out, aqueous phase dichloromethane extracted several times, merges organic phase,
Dry and be concentrated in vacuo to dry, obtain compound 3 (180 g), yield 100%.
Compound 3 (100 g, 0.436 mol) is dissolved in anhydrous tetrahydro furan (1.5 L), dripped while stirring
Add vinyl magnesium bromide (1.09 L, 1.09 mol, 1M) tetrahydrofuran solution.It is added dropwise, nitrogen protection lower 0oC reacts
30min, TLC (methylene chloride/methanol volume ratio=10/1, Rf=0.3) display reaction finishes, saturated aqueous ammonium chloride
Reaction is quenched, then is concentrated in vacuo most of tetrahydrofuran, then with 1N salt acid for adjusting pH to 3~4, aqueous phase dichloromethane
Alkane extracted several times, merge organic phase, anhydrous sodium sulfate drying, be concentrated in vacuo to it is dry obtain crude Compound 4 (112.2 g), receive
Rate 79.3%, is not further purified, and directly throws in next step.
Crude Compound 4 (113 g, 0.44 mol) is dissolved in anhydrous tetrahydro furan (1.5 L), and then 0oC points
Batch adds tetrahydrochysene lithium aluminium (20 g, 0.527 mol), then reacts at room temperature 1h.TLC (methylene chloride/methanol volume ratio=
10/1, Rf=0.8) display reaction finishes, and then successively uses water (20 mL), 15% sodium hydrate aqueous solution (20 mL)
Reaction is quenched with water (60 mL), 20min is stirred at room temperature, then filters, filter cake is washed for several times with dichloromethane, filtrate nothing
Aqueous sodium persulfate is dried, and is then concentrated in vacuo to dry.The crude product of oily silica gel chromatography (petrol ether/ethyl acetate volume
Than=10/1 ~ 5/1) obtain pure compound 5 (41.5 g), yield 38.8%.
Compound 5 (55 g, 0.226 mol) is dissolved in anhydrous tetrahydro furan (1.5 L), then protected in nitrogen
Under, 0oN-BuLi (90.4 mL, 0.226 mol, 2.5M) is added dropwise in C.It is added dropwise, stirs 30min, then addition pair in batches
Toluene sulfochloride (43.1 g, 0.226 mol), 0oC react 1h, be then added dropwise again n-BuLi (90.4 mL, 0.226 mol,
2.5M).1h, TLC (methylene chloride/methanol volume ratios=20/1, R are stirred at same temperaturef=0.8) display has been reacted
Finish.Reaction is quenched with saturated aqueous ammonium chloride, ethyl acetate extraction.Merge organic phase, dry, be then concentrated in vacuo to dry.
Gained crude product obtains pure compound 6 with silica gel chromatography (petrol ether/ethyl acetate volume ratio=50/1 ~ 20/1)
(33.3 g), yield 65.4%.
Compound 6 (28 g, 0.124 mol) is dissolved in acetonitrile (400 mL), then under room temperature condition respectively
Carbon tetrachloride/water (400 mL/340 mL), sodium acid carbonate (56.4 g, 0.671 mol) are added, and stirs 15min, then
Sodium metaperiodate (231.3 g, 1.08 mol), ruthenium trichloride (4.12 g, 0.02 mol) are separately added into again.React stirred
Night.TLC (petrol ether/ethyl acetate volume ratios=4/1, Rf=0) display reaction finishes.Reacting liquid filtering, mother liquor separation
Go out organic phase.Aqueous phase with 1N salt acid for adjusting pH value to 4~5, it is and anhydrous with dichloromethane extracted several times, merging machine phase, use
Sodium sulphate is dried, and is concentrated in vacuo to and dry is obtained compound 7 (25.7 g), yield 85%.
1MeOD, δ 4.566-4.564 (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 kind of synthetic method of 5- tertbutyloxycarbonyls -2- oxa- -5- azabicyclics [2.2.1] heptane -1- carboxylic acids, it is characterized in that
Comprise the following steps：First step reaction is reacted by compound 1 and Boc acid anhydrides under the conditions of sodium hydroxide solution, obtains compound
2, second step reaction aoxidizes generation compound 3, three-step reaction compound 3 and grignard with 2,2,6,6- tetramethyl piperidine oxides
Reagent reacting obtains compound 4, and four-step reaction tetrahydrochysene lithium aluminium reducing carboxylic acid 4 obtains compound 5, the 5th step reaction chemical combination
Thing 5 reacts to obtain compound 6 in two stages with n-BuLi and paratoluensulfonyl chloride, and six-step process compound 6 adds height
Sodium iodate and ruthenium trichloride, oxidation obtain final compound 7, and reaction equation is as follows：
。
A kind of 2. 5- tertbutyloxycarbonyls -2- oxa- -5- azabicyclics [2.2.1] heptane -1- carboxylic acids according to claim 1
Synthetic method, it is characterized in that：First step reaction temperature room temperature, tetrahydrofuran make solvent.
A kind of 3. 5- tertbutyloxycarbonyls -2- oxa- -5- azabicyclics [2.2.1] heptane -1- carboxylic acids according to claim 1
Synthetic method, it is characterized in that：Second step reaction temperature room temperature, dichloromethane make solvent.
A kind of 4. 5- tertbutyloxycarbonyls -2- oxa- -5- azabicyclics [2.2.1] heptane -1- carboxylic acids according to claim 1
Synthetic method, it is characterized in that：0 DEG C of three-step reaction temperature, tetrahydrofuran makees solvent.
A kind of 5. 5- tertbutyloxycarbonyls -2- oxa- -5- azabicyclics [2.2.1] heptane -1- carboxylic acids according to claim 1
Synthetic method, it is characterized in that：0 DEG C of four-step reaction temperature, tetrahydrofuran makees solvent.
A kind of 6. 5- tertbutyloxycarbonyls -2- oxa- -5- azabicyclics [2.2.1] heptane -1- carboxylic acids according to claim 1
Synthetic method, it is characterized in that, the 5th 0 DEG C of step reaction temperature, tetrahydrofuran makees solvent.
A kind of 7. 5- tertbutyloxycarbonyls -2- oxa- -5- azabicyclics [2.2.1] heptane -1- carboxylic acids according to claim 1
Synthetic method, it is characterized in that, six-step process temperature room temperature, acetonitrile as solvents.
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| 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 |
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