CN105503890A - 5-tert-butyloxycarbonyl octahydrofuro[3,2-c]pyridine-7-carboxylic acid synthesis method - Google Patents
5-tert-butyloxycarbonyl octahydrofuro[3,2-c]pyridine-7-carboxylic acid synthesis method Download PDFInfo
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Abstract
The present invention relates to a 5-tert-butyloxycarbonyl octahydrofuro[3,2-c]pyridine-7-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 1-bromo-2-chloroethane are subjected to an alkylation reaction to obtain a compound 2, an intramolecular ring closure reaction is performed to generate a compound 3, the double bond of the compound 3 is subjected to hydrogenation reducing to obtain a compound 4, and the compound 4 is subjected to hydrolysis to obtain a compound 5. The reaction formula is defined in the specification.
Description
Technical field
Compound 5-tertbutyloxycarbonyl octahydro furans [3,2-c] that the present invention relates to the synthetic method of pyridine-7-carboxylic acid.
Background technology
Compound 5-tertbutyloxycarbonyl octahydro furans [3,2-c] pyridine-7-carboxylic acid (CAS:1445951-87-0 and 1314399-22-8) and relevant derivative have widespread use in pharmaceutical chemistry and organic synthesis.Current 5-tertbutyloxycarbonyl octahydro furans [3,2-c] and pyridine-7-carboxylic acid synthesis comparatively difficulty.Therefore, need exploitation raw material to be easy to get, easy to operate, reaction is easy to control, the synthetic method that overall yield is applicable to.
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, 5-tertbutyloxycarbonyl octahydro furans [3,2-c] that yield is higher the synthetic method of pyridine-7-carboxylic acid.Mainly solve the technical problem not being applicable to Industrialized synthesis method at present.
Technical scheme of the present invention: 5-tertbutyloxycarbonyl octahydro furans [3,2-c] the synthetic method of pyridine-7-carboxylic acid, the present invention divides four steps, first by compound
1there is an alkylated reaction with bromochloroethane and obtain compound
2, be then that Intra-molecular condensation generates compound
3, hydro-reduction compound
3double bond after obtain compound
4, compound
4hydrolysis obtains compound
5.
In above-mentioned reaction, solvent: tetrahydrofuran (THF), methylene dichloride, ethanol, acetonitrile, toluene ethyl acetate, methyl alcohol, dioxane, methylene dichloride, triethylamine, water etc., catalyzer is palladium carbon etc., and first and second step reaction tetrahydrofuran (THF) makes solvent; Three-step reaction ethanol as solvent; Four-step reaction methanol as solvent.Alkali is potassium tert.-butoxide, sodium hydrogen, sodium hydroxide, potassium hydroxide etc.Second step reaction sodium hydrogen makes alkali; Four-step reaction sodium hydroxide makes alkali.
Beneficial effect of the present invention: the invention provides a kind of synthesis 5-tertbutyloxycarbonyl octahydro furans [3,2-c] and the method for pyridine-7-carboxylic acid, the method route is short, yield can up to 58.9%, and reaction is easy to amplify, easy to operate.
Embodiment
Reaction formula of the present invention is as follows:
。
Embodiment 1: by compound 1 (8.0g; 0.0295mol) be dissolved in tetrahydrofuran (THF) (60mL);-20 degrees Celsius are cooled to add potassium tert.-butoxide (8.8g; 0.0738mol); stir half an hour, then drip bromochloroethane (6.3g, 0.0443mol) under nitrogen protection; after adding, reaction is warmed up to 15 C overnight.TLC (sherwood oil: ethyl acetate volume ratio=5/1, R
f=0.5) display reaction is complete, reaction mixture saturated ammonium chloride solution (30mL) cancellation, and ethyl acetate (20mLx3) extracts.Concentrated after organic phase anhydrous sodium sulfate drying, residue uses column chromatography to purify, eluent ratio is (sherwood oil: ethyl acetate volume ratio=20/1), except the compound 2 (9.8g) obtaining yellow oil after desolventizing, and yield 100%.
Compound 2 (9.8g, 0.0295mol) is dissolved in tetrahydrofuran (THF) (80mL), under nitrogen protection and 0 degree Celsius, adds sodium hydrogen (1.77g, 0.0441mol), add post-heating backflow and spend the night.TLC (sherwood oil: ethyl acetate volume ratio=5/1, R
f=0.2) display reaction is complete.Reaction solution saturated ammonium chloride solution (30mL) cancellation, ethyl acetate (20mLx3) extracts.Concentrated after organic phase anhydrous sodium sulfate drying, residue uses column chromatography to purify, and eluent ratio is (sherwood oil: ethyl acetate volume ratio=20/1), except the compound 3 (6.4g) obtaining yellow oil after desolventizing, and yield 73%.
Compound 3 (6.4g, 0.0215mol) is dissolved in ethanol (150mL), add palladium charcoal (containing palladium weight percentage 10%, 1g), be heated to 50 degrees Celsius, pass into the hydrogen of 50Psi, reaction is spent the night.TLC (sherwood oil: ethyl acetate volume ratio=3/1, R
f=0.4) display reaction is complete.Reaction solution is by diatomite filtration, and concetrated under reduced pressure obtains the compound 4 (5.5g) of yellow oily, yield 85%.
Compound 4 (5.5g, 0.0185mol) is dissolved in methyl alcohol (50mL), adds sodium hydroxide (2.3g, 0.0550mol) and water (10mL), then stirred overnight at room temperature.TLC (sherwood oil: ethyl acetate volume ratio=3/1, R
f=0.4) display reaction is complete.Concentration of reaction solution, removing methyl alcohol.Dilution that residuum adds water (50mL), allows rear solid citric acid acidifying, until pH<5.Then ethyl acetate (20mLx3) is used to extract, concentrated after organic phase anhydrous sodium sulfate drying, obtain compound 5 (the 4.8g) yield 95% of yellow solid.
1 HNMR:CDCl
3，δ1.454(s,9H)1.626-1.682(m,1H)2.027-2.059(m,1H)2.501(m,1H)2.732–2.762(m,1H)3.045-3.341(m,1H)3.571(m,1H)3.840-4.191(m,3H)4.248-4.256(m,1H)。
Embodiment 2: by compound 1 (80g; 0.295mol) be dissolved in tetrahydrofuran (THF) (600mL);-20 degrees Celsius are cooled to add potassium tert.-butoxide (88g; 0.738mol); stir half an hour, then drip bromochloroethane (63g, 0.443mol) under nitrogen protection; after adding, reaction is warmed up to 15 C overnight.TLC (sherwood oil: ethyl acetate volume ratio=5/1, R
f=0.5) display reaction is complete, reaction mixture saturated ammonium chloride solution (300mL) cancellation, and ethyl acetate (200mLx3) extracts.Concentrated after organic phase anhydrous sodium sulfate drying, residue uses column chromatography to purify, and eluent ratio is (sherwood oil: ethyl acetate volume ratio=20/1), except the compound 2 (98g) obtaining yellow oil after desolventizing, and yield 100%.
Compound 2 (98g, 0.295mol) is dissolved in tetrahydrofuran (THF) (800mL), under nitrogen protection and 0 degree Celsius, adds sodium hydrogen (17.7g, 0.441mol), add post-heating backflow and spend the night.TLC (sherwood oil: ethyl acetate volume ratio=5/1, R
f=0.2) display reaction is complete.Reaction solution saturated ammonium chloride solution (300mL) cancellation, ethyl acetate (200mLx3) extracts.Concentrated after organic phase anhydrous sodium sulfate drying, residue uses column chromatography to purify, and eluent ratio is (sherwood oil: ethyl acetate volume ratio=20/1), except the compound 3 (64g) obtaining yellow oil after desolventizing, and yield 73%.
Compound 3 (64g, 0.215mol) is dissolved in ethanol (1500mL), add palladium charcoal (containing palladium weight percentage 10%, 10g), be heated to 50 degrees Celsius, pass into the hydrogen of 50Psi, reaction is spent the night.TLC (sherwood oil: ethyl acetate volume ratio=3/1, R
f=0.4) display reaction is complete.Reaction solution is by diatomite filtration, and concetrated under reduced pressure obtains the compound 4 (55g) of yellow oily, yield 85%.
Compound 4 (55g, 0.196mol) is dissolved in methyl alcohol (500mL), adds sodium hydroxide (23g, 0.588mol) and water (100mL), then stirred overnight at room temperature.TLC (sherwood oil: ethyl acetate volume ratio=3/1, R
f=0) display reaction is complete.Concentration of reaction solution, removing methyl alcohol.Dilution that residuum adds water (500mL), allows rear solid citric acid acidifying, until pH<5.Then ethyl acetate (200mLx3) is used to extract, concentrated after organic phase anhydrous sodium sulfate drying, obtain compound 5 (the 48g) yield 95% of yellow solid.
1 HNMR:CDCl
3，δ1.454(s,9H)1.626-1.682(m,1H)2.027-2.059(m,1H)2.501(m,1H)2.732–2.762(m,1H)3.045-3.341(m,1H)3.571(m,1H)3.840-4.191(m,3H)4.248-4.256(m,1H)。
Embodiment 3: by compound 1 (400g; 1.475mol) be dissolved in tetrahydrofuran (THF) (4.0L);-20 degrees Celsius are cooled to add potassium tert.-butoxide (440g; 3.69mol); stir half an hour, then drip bromochloroethane (315g, 2.215mol) under nitrogen protection; after adding, reaction is warmed up to 15 C overnight.TLC (sherwood oil: ethyl acetate volume ratio=5/1, R
f=0.5) display reaction is complete, reaction mixture saturated ammonium chloride solution (1.0L) cancellation, and ethyl acetate (1.0Lx3) extracts.Concentrated after organic phase anhydrous sodium sulfate drying, residue uses column chromatography to purify, eluent ratio is (sherwood oil: ethyl acetate volume ratio=20/1), except the compound 2 (490g) obtaining yellow oil after desolventizing, and yield 100%.
Compound 2 (490g, 1.475mol) is dissolved in tetrahydrofuran (THF) (4.0L), under nitrogen protection and 0 degree Celsius, adds sodium hydrogen (177g, 4.41mol), add post-heating backflow and spend the night.TLC (sherwood oil: ethyl acetate volume ratio=5/1, R
f=0.2) display reaction is complete.Reaction solution saturated ammonium chloride solution (500mL) cancellation, ethyl acetate (300mLx3) extracts.Concentrated after organic phase anhydrous sodium sulfate drying, residue uses column chromatography to purify, and eluent ratio is (sherwood oil: ethyl acetate volume ratio=20/1), except the compound 3 (320g) obtaining yellow oil after desolventizing, and yield 73%.
Compound 3 (320g, 1.077mol) is dissolved in ethanol (6.4L), add palladium charcoal (containing palladium weight percentage 10%, 40g), be heated to 50 degrees Celsius, pass into the hydrogen of 50Psi, reaction is spent the night.TLC (sherwood oil: ethyl acetate volume ratio=3/1, R
f=0.4) display reaction is complete.Reaction solution is by diatomite filtration, and concetrated under reduced pressure obtains the compound 4 (275g) of yellow oily, yield 85%.
Compound 4 (275g, 0.92mol) is dissolved in methyl alcohol (2.0L), adds sodium hydroxide (115g, 2.94mol) and water (700mL), then stirred overnight at room temperature.TLC (sherwood oil: ethyl acetate volume ratio=3/1, R
f=0) display reaction is complete.Concentration of reaction solution, removing methyl alcohol.Dilution that residuum adds water (2.0L), allows rear solid citric acid acidifying, until pH<5.Then ethyl acetate (500mLx3) is used to extract, concentrated after organic phase anhydrous sodium sulfate drying, obtain compound 5 (the 240g) yield 95% of yellow solid.
1 HNMR:CDCl
3，δ1.454(s,9H)1.626-1.682(m,1H)2.027-2.059(m,1H)2.501(m,1H)2.732–2.762(m,1H)3.045-3.341(m,1H)3.571(m,1H)3.840-4.191(m,3H)4.248-4.256(m,1H)。
Claims (5)
1. 5-tertbutyloxycarbonyl octahydro furans [3,2-c] the synthetic method of pyridine-7-carboxylic acid, is characterized in that comprising the following steps: first by compound
1there is an alkylated reaction with bromochloroethane and obtain compound
2, compound 2 Intra-molecular condensation generates compound
3, hydro-reduction compound
3double bond after obtain compound
4, compound
4hydrolysis obtains compound
5; Reaction formula is as follows:
。
2. 5-tertbutyloxycarbonyl octahydro furans [3 according to claim 1; 2-c] and the synthetic method of pyridine-7-carboxylic acid, it is characterized in that: the first step reaction tetrahydrofuran (THF) makes solvent, by compound 1 with after potassium tert.-butoxide process; drip bromochloroethane under nitrogen protection, maintain 15 DEG C of reactions and spend the night.
3. 5-tertbutyloxycarbonyl octahydro furans [3,2-c] according to claim 1 the synthetic method of pyridine-7-carboxylic acid, is characterized in that: compound 2 is dissolved in tetrahydrofuran (THF) by second step reaction, and lower 0 degree Celsius of nitrogen protection adds sodium hydrogen, and reaction is spent the night.
4. 5-tertbutyloxycarbonyl octahydro furans [3,2-c] according to claim 1 the synthetic method of pyridine-7-carboxylic acid, is characterized in that: three-step reaction ethanol as solvent, by compound 3 and palladium carbon at 50 c, and the hydrogen treat of pressurization 50Psi.
5. 5-tertbutyloxycarbonyl octahydro furans [3 according to claim 1,2-c] and the synthetic method of pyridine-7-carboxylic acid, it is characterized in that: compound 4 is dissolved in methyl alcohol by four-step reaction, at room temperature react with sodium hydroxide and spend the night, after process, obtain compound 5.
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| CN107383034A (en) * | 2017-06-29 | 2017-11-24 | 上海药明康德新药开发有限公司 | The synthetic method of (tertbutyloxycarbonyl) octahydro of racemic 5 furans simultaneously [3,2 c] pyridine 3a carboxylic acids |
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| WO2011106276A1 (en) * | 2010-02-25 | 2011-09-01 | Merck Sharp & Dohme Corp. | Task channel antagonists |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107383034A (en) * | 2017-06-29 | 2017-11-24 | 上海药明康德新药开发有限公司 | The synthetic method of (tertbutyloxycarbonyl) octahydro of racemic 5 furans simultaneously [3,2 c] pyridine 3a carboxylic acids |
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Application publication date: 20160420 |