CN105418620B - A kind of synthetic method of 4- (tertbutyloxycarbonyl) octahydros furans simultaneously [3,2-b] pyridine -6- carboxylic acids - Google Patents
A kind of synthetic method of 4- (tertbutyloxycarbonyl) octahydros furans simultaneously [3,2-b] pyridine -6- carboxylic acids Download PDFInfo
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Abstract
The present invention relates to a kind of synthetic method of 4 (tertbutyloxycarbonyl) octahydro furans simultaneously 6 carboxylic acid of [3,2 b] pyridine, the technical problem currently without suitable Industrialized synthesis method is mainly solved.Six steps of the present invention point; compound 2 is obtained by the esterification of compound 1 first; then upper Iod R generation compound 3; compound 4 is obtained after 3 acetylation of compound; coupling occurs again and obtains compound 5, cyclization obtains compound 6, hydrogenates to obtain compound 7; then compound 8 is obtained with Boc anhydride reactions, final compound 9 is obtained after hydrolysis.Reaction equation is as follows：
Description
Technical field
(the CAS of compound 4- (tertbutyloxycarbonyl) octahydros furans of the present invention simultaneously [3,2-b] pyridine -6- carboxylic acids:
1314388-60-7) synthetic method.
Background technology
Compound 4- (tertbutyloxycarbonyl) octahydros furans simultaneously [3,2-b] pyridine -6- carboxylic acids and relevant derivative in medicine
There is extensive use in chemistry and organic synthesis, market sale is fine.4- (tertbutyloxycarbonyl) octahydros furans is simultaneously [3,2-b] at present
The synthesis of pyridine -6- carboxylic acids is more difficult.Easy to operate therefore, it is necessary to develop a raw material to be easy to get, reaction is easily controllable, always
Body yield is adapted to, and is adapted to the synthetic method of industrialized production.
The content of the invention
It is easy to get the purpose of the present invention is exploitation is a kind of with raw material, it is easy to operate, react easily controllable, the higher 4- of yield
The synthetic method of (tertbutyloxycarbonyl) octahydro furans simultaneously [3,2-b] pyridine -6- carboxylic acids.Mainly solve currently without suitable industrialization
The technical problem of synthetic method.
Technical scheme：The synthesis side of 4- (tertbutyloxycarbonyl) octahydros furans simultaneously [3,2-b] pyridine -6- carboxylic acids
Method, six steps of the present invention point, obtain compound 2 by the esterification of compound 1 first, then upper Iod R generation compound 3, compound 3
Compound 4 is obtained after acetylation, then coupling reaction occurs and obtains compound 5, cyclization obtains compound 6, hydrogenates to obtain compound 7, so
Compound 8 is obtained with Boc anhydride reactions afterwards, final compound 9 is obtained after hydrolysis；
。
The Chinese paraphrase that the present invention abridges：Boc tertbutyloxycarbonyls；Ac acetyl group, solvent is ethanol, tetrahydrofuran, ice second
A kind of or wherein two kinds of mixed solvent in acid, methanol, dichloromethane, water, hydrogenation catalyst is palladium carbon, double（Triphenyl
Phosphine）One kind in palladium chloride, preferably palladium carbon.
First step reaction is refluxed overnight；Second step reaction need to carry out in water, reaction temperature room temperature（It is 15-30 DEG C, rear same）；
Three-step reaction solvent is dichloromethane, and reaction temperature is 0 DEG C；4th step solvent selects tetrahydrofuran, adds double (triphenyls
Phosphine) palladium chloride, iodate Asia ketone, triethylamine does alkali, and reaction temperature is room temperature；5th step solvent selects tetrahydrofuran, reaction temperature
Spend for 10-20 DEG C；6th step solvent selects ethanol or the mixed solvent of methanol and glacial acetic acid, and room temperature reaction is overnight.
Beneficial effects of the present invention：The present invention provides one kind synthesis 4- (tertbutyloxycarbonyl) octahydros furans simultaneously [3,2-b]
The method of pyridine -6- carboxylic acids, this method route is short, and raw material is cheap and is readily obtained, and environmental pollution is small, high income up to 28.7%,
Reaction is easy to amplify, easy to operate.
Embodiment
Reaction equation of the present invention is as follows：
。
Embodiment 1：Compound 1 (7.11 g, 51.1 mmol) is dissolved in ethanol (300 mL), thionyl chloride is added dropwise in room temperature
After (36 mL) is added, reaction is refluxed overnight.TLC (ethyl acetate=1, Rf=0.8) display reaction finishes, reaction mixture
Decompression is spin-dried for, residue add saturated aqueous sodium carbonate make pH=7 obtain compound 2 be directly used in next step.
The solution of compound 2 is added into water (150 mL), adds sodium carbonate (7.33 g, 0.307 mol) and iodine (9.65
G, 0.153 mol), when room temperature reaction 2 is small.TLC (petroleum ethers：Ethyl acetate volume ratio=1/1, Rf=0.8) display reaction
Finishing, reaction solution, which adds 1N hydrochloric acid, makes pH=7 separate out solid, and filtering decompression is spin-dried for obtaining yellow solid compound 3 (9.3 g),
82 % of yield.
1CDCl3, 4.35-4.40 (m, 2 H) 7.57 of δ 1.36-1.40 (m, 3 H) 3.91 (s, 1 H)
(s, 1 H) 8.36 (s, 1 H)。
Compound 3 (9.25 g, 31.5 mmol) is dissolved in dichloromethane (100 mL), add triethylamine (12.80 g,
0.126 mol), chloroacetic chloride (5 g, 63.1 mmol) is added dropwise in zero degrees celsius, after adding, when zero degrees celsius reaction 0.5 is small.TLC
(petroleum ether：Ethyl acetate volume ratio=3/1, Rf=0.7) display reaction finishes.Reaction solution extracts after adding water, and organic phase is used
Anhydrous sodium sulfate drying is spin-dried for obtaining brown solid compound 4 (9.1 g), yield 84.3%.
Will double (triphenylphosphine) palladium chlorides (127 mg, 0.18 mmol), cuprous iodide (67 mg, 0.36 mmol),
Triethylamine (9.43 g, 93.4 mmol) and compound 4 (2 g) are dissolved in dry tetrahydrofuran (50 mL), are added dropwise to front three
Base silico acetylene (0.74 g, 8.09 mmol) in the solution of tetrahydrofuran (5 mL), add room temperature reaction 1 it is small when.TLC (oil
Ether：Ethyl acetate volume ratio=5/1, Rf=0.6) display reaction finishes.Reaction solution is filtered by diatomite, under filtrate decompression
Grey oily compound 5 is concentrated to give to be directly used in next step.
Compound 5 is dissolved in methanol (50 mL), potassium fluoride (1.24 g, 22.4 mmol) is added portionwise under 10 degrees Celsius,
After adding, when room temperature reaction 1 is small.TLC (petroleum ethers：Ethyl acetate volume ratio=5/1, Rf=0.6) display reaction finishes.Instead
Answer liquid to be filtered by diatomite, concentrated under filtrate decompression, chromatography obtains yellow solid compound 6 (3.5 g), yield
50%。
1CDCl3, 4.41-4.49 (m, 2 H) 7.10 of δ 1.41-1.44 (m, 3 H) 3.97 (s, 1 H)
– 7.11 (d, 1 H) 8.29 – 8.30 (d, 1 H) 8.48 (s, 1 H) 9.09 (d, 1 H)。
Compound 6 (1.66 g, 5.7 mmol) is dissolved in methanol (3 mL) and glacial acetic acid (20 mL), palladium charcoal is added and (contains
Palladium weight percentage 10%, 0.8 g), is heated to 80 degrees Celsius, the hydrogen of 5Mpa is passed through, when reaction 40 is small.TLC (oil
Ether：Ethyl acetate volume ratio=1/1, Rf=0.1) display reaction finishes.Yellow oily is concentrated to give under reaction solution decompression
Compound 7 is directly used in next step.
Compound 7 is dissolved in dichloromethane (50 mL) and triethylamine (7 mL), add di-tert-butyl dicarbonate (2.06 g,
9.56 mol), after adding, when room temperature reaction 0.5 is small.TLC (dichloromethane：Methanol volume ratio=10/1, Rf=0.8) show
Reaction finishes.Reaction solution is washed, and being concentrated to give yellow oily compound 8 under dry decompression is directly used in next step.
Compound 8 is dissolved in methanol (10 mL) and water (10 mL), adds sodium hydroxide (0.45 g, 11.25 mmol),
After adding, room temperature reaction is overnight.TLC (petroleum ethers：Ethyl acetate volume ratio=3/1, Rf=0.1) display reaction finishes.Instead
The lower most of methanol of concentration of liquid decompression is answered, ethyl acetate is washed, and water is extracted with ethyl acetate drying and is concentrated under reduced pressure to give after being mutually acidified
White solid (2.2 g), yield 91%.
1CDCl3, 2.16-2.30 (m, 1 H) 2.75 of δ 1.46 (s, 9 H) 1.83-2.08 (m, 3 H)
(dt, J=12.35, 6.17 Hz, 1 H) 3.27 (dd, J=13.67, 6.17 Hz, 1 H) 3.59 - 3.73 (m,
1 H) 3.96 - 4.15 (m, 3 H) 4.54 (q, J=7.06 Hz, 1 H)。
Embodiment 2：Compound 1 (71.1 g, 511 mmol) is dissolved in ethanol (1500 mL), thionyl chloride is added dropwise in room temperature
After (360 mL) is added, reaction is refluxed overnight.TLC (ethyl acetate=1, Rf=0.8) display reaction finishes, reaction mixture
Decompression is spin-dried for, residue add saturated aqueous sodium carbonate make pH=7 obtain compound 2 be directly used in next step.
The solution of compound 2 is added into water (1500 mL), adds sodium carbonate (73.3 g, 3.07 mol) and iodine (96.5
G, 1.53 mol), when room temperature reaction 2 is small.TLC (petroleum ethers：Ethyl acetate volume ratio=1/1, Rf=0.8) display reaction
Finishing, reaction solution, which adds 1N hydrochloric acid, makes pH=7 separate out solid, and filtering decompression is spin-dried for obtaining yellow solid compound 3 (93.3 g),
82 % of yield.
1CDCl3, 4.35-4.40 (m, 2 H) 7.57 of δ 1.36-1.40 (m, 3 H) 3.91 (s, 1 H)
(s, 1 H) 8.36 (s, 1 H)。
Compound 3 (92.5 g, 315 mmol) is dissolved in dichloromethane (1000 mL), add triethylamine (128.0 g,
1.26 mol), chloroacetic chloride (50 g, 631 mmol) is added dropwise in zero degrees celsius, after adding, when zero degrees celsius reaction 0.5 is small.TLC
(petroleum ether：Ethyl acetate volume ratio=3/1, Rf=0.7) display reaction finishes.Reaction solution extracts after adding water, and organic phase is used
Anhydrous sodium sulfate drying is spin-dried for obtaining brown solid compound 4 (91.3 g), yield 84.5%.
Will double (triphenylphosphine) palladium chlorides (1.27 g, 1.8 mmol), cuprous iodide (670 mg, 3.6 mmol),
Triethylamine (94.3 g, 934 mmol) and compound 4 (20 g) are dissolved in dry tetrahydrofuran (500 mL), are added dropwise to three
Methyl silico acetylene (7.4 g, 80.9 mmol) in the solution of tetrahydrofuran (50 mL), add room temperature reaction 1 it is small when.TLC (stones
Oily ether：Ethyl acetate volume ratio=5/1, Rf=0.6) display reaction finishes.Reaction solution is filtered by diatomite, filtrate decompression
Under be concentrated to give grey oily compound 5 be directly used in next step.
Compound 5 is dissolved in methanol (500 mL), potassium fluoride (12.4 g, 224 mmol) is added portionwise under 10 degrees Celsius,
After adding, when room temperature reaction 1 is small.TLC (petroleum ethers：Ethyl acetate volume ratio=5/1, Rf=0.6) display reaction finishes.Instead
Answer liquid to be filtered by diatomite, concentrated under filtrate decompression, chromatography obtains yellow solid compound 6 (35.5 g), yield
51%。
1CDCl3, 4.41-4.49 (m, 2 H) 7.10 of δ 1.41-1.44 (m, 3 H) 3.97 (s, 1 H)
– 7.11 (d, 1 H) 8.29 – 8.30 (d, 1 H) 8.48 (s, 1 H) 9.09 (d, 1 H)。
Compound 6 (16.6 g, 57 mmol) is dissolved in methanol (30 mL) and glacial acetic acid (200 mL), palladium charcoal is added and (contains
Palladium weight percentage 10%, 8 g), is heated to 80 degrees Celsius, the hydrogen of 5Mpa is passed through, when reaction 40 is small.TLC (oil
Ether：Ethyl acetate volume ratio=1/1, Rf=0.1) display reaction finishes.Yellow oily is concentrated to give under reaction solution decompression
Compound 7 is directly used in next step.
Compound 7 is dissolved in dichloromethane (500 mL) and triethylamine (70 mL), adds di-tert-butyl dicarbonate (20.6
G, 95.6 mol), after adding, when room temperature reaction 0.5 is small.TLC (dichloromethane：Methanol volume ratio=10/1, Rf = 0.8)
Display reaction finishes.Reaction solution is washed, and being concentrated to give yellow oily compound 8 under dry decompression is directly used in next step.
Compound 8 is dissolved in methanol (100 mL) and water (100 mL), add sodium hydroxide (4.5 g, 112.5
Mmol), after adding, room temperature reaction is overnight.TLC (petroleum ethers：Ethyl acetate volume ratio=3/1, Rf=0.1) display has been reacted
Finish.The lower most of methanol of concentration of reaction solution decompression, ethyl acetate are washed, and water is extracted with ethyl acetate drying and is concentrated under reduced pressure after being mutually acidified
Obtain white solid (22.3 g), yield 91%.
1CDCl3, 2.16-2.30 (m, 1 H) 2.75 of δ 1.46 (s, 9 H) 1.83-2.08 (m, 3 H)
(dt, J=12.35, 6.17 Hz, 1 H) 3.27 (dd, J=13.67, 6.17 Hz, 1 H) 3.59 - 3.73 (m,
1 H) 3.96 - 4.15 (m, 3 H) 4.54 (q, J=7.06 Hz, 1 H)。
Embodiment 3：Compound 1 (711 g, 9.11 mol) is dissolved in ethanol (5 L), thionyl chloride (3.6 is added dropwise in room temperature
L after) adding, reaction is refluxed overnight.TLC (ethyl acetate=1, Rf=0.8) display reaction finishes, reaction mixture decompression rotation
Dry, residue, which adds saturated aqueous sodium carbonate and pH=7 is obtained compound 2, to be directly used in next step.
The solution of compound 2 is added into water (15 L), add sodium carbonate (733 g, 30.7 mol) and iodine (965 g,
15.3 mol), when room temperature reaction 2 is small.TLC (petroleum ethers：Ethyl acetate volume ratio=1/1, Rf=0.8) display has been reacted
Finish, reaction solution, which adds 1N hydrochloric acid, makes pH=7 separate out solid, and filtering decompression is spin-dried for obtaining yellow solid compound 3 (925 g), receives
82.5 % of rate.
1CDCl3, 4.35-4.40 (m, 2 H) 7.57 of δ 1.36-1.40 (m, 3 H) 3.91 (s, 1 H)
(s, 1 H) 8.36 (s, 1 H)。
Compound 3 (925 g, 3.15 mol) is dissolved in dichloromethane (5 L), add triethylamine (1280 g, 12.6
Mol), chloroacetic chloride (500 g, 6.31 mol) is added dropwise in zero degree, after adding, when zero degrees celsius reaction 0.5 is small.TLC (petroleum ethers：Second
Acetoacetic ester volume ratio=3/1, Rf=0.7) display reaction finishes.Reaction solution extracts after adding water, organic phase anhydrous sodium sulfate
Drying is spin-dried for obtaining brown solid compound 4 (875 g), yield 83.3%.
Will double (triphenylphosphine) palladium chlorides (12.7 g, 0.018 mol), cuprous iodide (6.7 g, 0.036 mol),
Triethylamine (943 g, 9.34 mol) and compound 4 (200 g) are dissolved in dry tetrahydrofuran (500 mL), are added dropwise to three
Methyl silico acetylene (74 g, 0.809 mol) in the solution of tetrahydrofuran (500 mL), add room temperature reaction 1 it is small when.TLC (stones
Oily ether：Ethyl acetate volume ratio=5/1, Rf=0.6) display reaction finishes.Reaction solution is filtered by diatomite, filtrate decompression
Under be concentrated to give grey oily compound 5 be directly used in next step.
Compound 5 is dissolved in methanol (1500 mL), potassium fluoride (124 g, 2.24 mol) is added portionwise under 10 degrees Celsius,
After adding, when room temperature reaction 1 is small.TLC (petroleum ethers：Ethyl acetate volume ratio=5/1, Rf=0.6) display reaction finishes.Instead
Answer liquid to be filtered by diatomite, concentrated under filtrate decompression, chromatography obtains yellow solid compound 6 (321 g), yield
47%。
1CDCl3, 4.41-4.49 (m, 2 H) 7.10 of δ 1.41-1.44 (m, 3 H) 3.97 (s, 1 H)
– 7.11 (d, 1 H) 8.29 – 8.30 (d, 1 H) 8.48 (s, 1 H) 9.09 (d, 1 H)。
Compound 6 (166 g, 0.57 mol) is dissolved in ethanol (300 mL) and glacial acetic acid (2 L), palladium charcoal is added and (contains palladium
Weight percentage 10%, 80g), 80 degrees Celsius are heated to, the hydrogen of 5Mpa is passed through, when reaction 40 is small.TLC (petroleum ethers：
Ethyl acetate volume ratio=1/1, Rf=0.1) display reaction finishes.The change of yellow oily is concentrated to give under reaction solution decompression
Compound 7 is directly used in next step.
Compound 7 is dissolved in dichloromethane (1500 mL) and triethylamine (700 mL), adds di-tert-butyl dicarbonate (206
G, 0.956 mol), after adding, when room temperature reaction 0.5 is small.TLC (dichloromethane：Methanol volume ratio=10/1, Rf = 0.8)
Display reaction finishes.Reaction solution is washed, and being concentrated to give yellow oily compound 8 under dry decompression is directly used in next step.
Compound 8 is dissolved in methanol (1000 mL) and water (1000 mL), adds sodium hydroxide (45g, 1.125 mol),
After adding, room temperature reaction is overnight.TLC (petroleum ethers：Ethyl acetate volume ratio=3/1, Rf=0.1) display reaction finishes.Instead
The lower most of methanol of concentration of liquid decompression is answered, ethyl acetate is washed, and water is extracted with ethyl acetate drying and is concentrated under reduced pressure to give after being mutually acidified
White solid (212 g), yield 90%.
1CDCl3, 2.16-2.30 (m, 1 H) 2.75 of δ 1.46 (s, 9 H) 1.83-2.08 (m, 3 H)
(dt, J=12.35, 6.17 Hz, 1 H) 3.27 (dd, J=13.67, 6.17 Hz, 1 H) 3.59 - 3.73 (m,
1 H) 3.96 - 4.15 (m, 3 H) 4.54 (q, J=7.06 Hz, 1 H)。
Claims (8)
1. a kind of synthetic method of 4- (tertbutyloxycarbonyl) octahydros furans simultaneously [3,2-b] pyridine -6- carboxylic acids, it is characterized in that including with
Lower step：Compound 2 is obtained by the esterification of compound 1 first, then upper Iod R generation compound 3, after 3 acetylation of compound
To compound 4, then coupling occurs and obtains compound 5, cyclization obtains compound 6, hydrogenates to obtain compound 7, then with Boc anhydride reactions
Compound 8 is obtained, final compound is obtained after hydrolysis, reaction equation is as follows：
。
A kind of 2. synthesis of 4- (tertbutyloxycarbonyl) octahydros furans according to claim 1 simultaneously [3,2-b] pyridine -6- carboxylic acids
Method, it is characterized in that：Solvent is ethanol, tetrahydrofuran, glacial acetic acid, methanol, dichloromethane, a kind of in water or wherein two kinds mixed
Bonding solvent.
A kind of 3. synthesis of 4- (tertbutyloxycarbonyl) octahydros furans according to claim 1 simultaneously [3,2-b] pyridine -6- carboxylic acids
Method, it is characterized in that：First step reaction is refluxed overnight.
A kind of 4. synthesis of 4- (tertbutyloxycarbonyl) octahydros furans according to claim 1 simultaneously [3,2-b] pyridine -6- carboxylic acids
Method, it is characterized in that：Second step reaction need to carry out in water, reaction temperature room temperature.
A kind of 5. synthesis of 4- (tertbutyloxycarbonyl) octahydros furans according to claim 1 simultaneously [3,2-b] pyridine -6- carboxylic acids
Method, it is characterized in that：Three-step reaction solvent is dichloromethane, and reaction temperature is 0 DEG C.
A kind of 6. synthesis of 4- (tertbutyloxycarbonyl) octahydros furans according to claim 1 simultaneously [3,2-b] pyridine -6- carboxylic acids
Method, it is characterized in that：4th step solvent selects tetrahydrofuran, adds double (triphenylphosphine) palladium chlorides, iodate Asia ketone, triethylamine
Alkali is done, reaction temperature is room temperature.
A kind of 7. conjunction of 4- (tertbutyloxycarbonyl) octahydros furans according to claim 1 simultaneously [3,2-b] pyridine -6- carboxylic acids
Into method, it is characterized in that：5th step solvent selects tetrahydrofuran, and reaction temperature is 10-20 DEG C.
A kind of 8. synthesis of 4- (tertbutyloxycarbonyl) octahydros furans according to claim 1 simultaneously [3,2-b] pyridine -6- carboxylic acids
Method, it is characterized in that：6th step solvent selects ethanol or the mixed solvent of methanol and glacial acetic acid, and room temperature reaction is overnight.
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| CN107383035B (en) * | 2017-06-29 | 2019-06-25 | 上海合全药业股份有限公司 | 2- ((1S3aR7aR) -5- tertbutyloxycarbonyl tetrahydrofuran simultaneously [3,4] piperidines -1) acetic acid preparation method |
| CN114213424B (en) * | 2021-12-30 | 2023-05-26 | 杭州高光制药有限公司 | Synthesis method of furan [3,2-b ] pyridine derivative |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4808595A (en) * | 1986-12-24 | 1989-02-28 | Merck & Co., Inc. | Furopyridine sulfonamides and their opthalmological compositions |
| WO2013163466A1 (en) * | 2012-04-25 | 2013-10-31 | Presidio Pharmaceuticals, Inc. | Inhibitors of hepatitis c virus |
-
2014
- 2014-09-23 CN CN201410488804.0A patent/CN105418620B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4808595A (en) * | 1986-12-24 | 1989-02-28 | Merck & Co., Inc. | Furopyridine sulfonamides and their opthalmological compositions |
| WO2013163466A1 (en) * | 2012-04-25 | 2013-10-31 | Presidio Pharmaceuticals, Inc. | Inhibitors of hepatitis c virus |
Non-Patent Citations (1)
| Title |
|---|
| Solid-Phase Syntheses of Furopyridine and Furoquinoline Systems;Pablo Cironi等，;《Org. Lett.》;20040326;第6卷(第9期);第1405-1408页 * |
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