CN110498779A - A kind of preparation method for disliking fourth cycloalkanes -3- base methanol - Google Patents
A kind of preparation method for disliking fourth cycloalkanes -3- base methanol Download PDFInfo
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- CN110498779A CN110498779A CN201910664444.8A CN201910664444A CN110498779A CN 110498779 A CN110498779 A CN 110498779A CN 201910664444 A CN201910664444 A CN 201910664444A CN 110498779 A CN110498779 A CN 110498779A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D305/04—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D305/06—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring atoms
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Abstract
The present invention relates to a kind of preparation methods for disliking fourth cycloalkanes -3- base methanol, the technical issues of mainly solution currently without suitable Industrialized synthesis method.The present invention is divided into three steps: compound 1 and triphenylphosphine then obtain compound 4 with compound 3 at compound 2 in ethyl acetate under the action of cesium carbonate first, then obtain product 5 after hydroxide palladium carbon acts on hydro-reduction.
Description
Technical field
The present invention relates to the synthetic methods for disliking fourth cycloalkanes -3- base methanol (CAS:6246-06-6).
Background technique
Dislike fourth cycloalkanes -3- base methanol and relevant derivative has extensive use in pharmaceutical chemistry and organic synthesis.Mesh
It is preceding about disliking the synthesis report of fourth cycloalkanes -3- base methanol seldom, similar document reaction there are certain risk and route it is long, receive
Rate is lower.Therefore it needs to develop a raw material to be easy to get, it is easy to operate, react easily controllable, the suitable synthetic method of overall yield.
Summary of the invention
It is easy to operate the purpose of the present invention is developing one kind to be easy to get with raw material, react easily controllable, the higher evil of yield
The synthetic method of fourth cycloalkanes -3- base methanol.The technical issues of mainly solving currently without suitable Industrialized synthesis method.
Technical solution of the present invention: a kind of preparation method for disliking fourth cycloalkanes -3- base methanol includes the following steps, the present invention
Divide three steps, the first step, compound 1 and triphenylphosphine generate compound 2, second step, compound 2 and compound in ethyl acetate
3 obtain compound 4 in tetrahydrofuran under the action of cesium carbonate, third step, and compound 4 is through hydroxide palladium carbon hydrogen in methyl alcohol
Product 5 is obtained after changing reduction, reaction equation is as follows:
Reaction 10-20 hours of 50 DEG C of the first step, preferably 18 hours；Reaction 10-20 hours of 50 DEG C of second step, preferably 18 hours；The
Three 50 DEG C of steps are reacted 18 hours.
Beneficial effects of the present invention: the present invention provides a kind of method that fourth cycloalkanes -3- base methanol is disliked in synthesis, this method is closed
Short at route, yield may be up to 18.7%, and reaction is easy to amplify, easy to operate, have industrial applications prospect.
Specific embodiment
Reaction equation of the present invention is as follows:
Embodiment 1:a, compound 1(550 g, 3.51 mol) it is dissolved in ethyl acetate (2.2 L) and is stirred at room temperature 20 minutes,
Then triphenylphosphine (1.4 kg, 5.3 mol) is added at one time in reaction solution at room temperature.Reaction solution is heated to 50 DEG C and stirs
It mixes 18 hours.Reaction depressurizes suction filtration after being cooled to room temperature, and filter cake is eluted with methyl tertiary butyl ether(MTBE), and filter cake decompression drying obtains product
Compound as white solid 2(1.3 kg), yield 88%.
δ7.55 - 7.86 (m, 15 H) 7.25 (s, 5 H) 5.96 (d, J=3.97 Hz, 2 H) 4.96
(s, 2 H)。
B, cesium carbonate (622 g, 1.9 mol) is added to compound 2(400 g, 0.95 mol at room temperature) tetrahydro
In furans (1.6 L) solution.Reaction solution stirs half an hour time at room temperature and compound 3(69 g, 0.95 mol) is added to reaction
In liquid, reaction solution is warming up to 50 DEG C and stirs 18 hours.Reaction solution is cooled to depressurize after room temperature and is filtered.Filter cake uses ethyl acetate
(300 mL x 3) elution, the filtrate decompression after merging are concentrated to get crude product.Crude product chromatographs (petroleum ether/acetic acid using column
Ethyl ester volume ratio=1/0-10/1) isolated yellow oily compound 4(44 g), yield 26%.
δ7.28 - 7.43 (m, 5 H) 5.89 - 5.98 (m, 1 H) 5.29 (q, J=2.50 Hz, 1 H)
5.18 (q, J=2.35 Hz, 1 H) 4.77 (s, 1 H)。
C, methanol (100 mL) is dispersed by hydroxide palladium carbon (3 g), then adds compound 4(11 g, 65 mmol)
Enter into reaction solution, reaction is vacuumized using H2Displacement 3 times.H of the reaction solution in 50psi2Under conditions of 50 DEG C of stirrings it is 18 small
When.TLC shows raw material end of reaction.Reaction solution is depressurized and is filtered, filter cake is eluted using methanol (50 mL), the filtrate after merging
It is concentrated under reduced pressure to give crude product.Crude product obtains colorless and transparent oily compound 5(4.6 using water pump vacuum distillation (75-81 DEG C)
G), yield 90%.
δ4.78 (dd, J=7.94, 6.17 Hz, 1 H) 4.47 (t, J=5.95 Hz, 1 H) 3.76 (d, J=
6.62 Hz, 1 H) 3.05 - 3.20 (m, 1 H)。
Embodiment 2:a, compound 1(5.5 kg, 35.1 mol) it is dissolved in ethyl acetate (22 L) and is stirred at room temperature 20 points
Triphenylphosphine (14 kg, 53 mol) is then added at one time in reaction solution by clock at room temperature.Reaction solution is heated to 50 DEG C and stirs
It mixes 18 hours.Reaction depressurizes suction filtration after being cooled to room temperature, and filter cake is eluted with methyl tertiary butyl ether(MTBE), and filter cake decompression drying obtains product
Compound as white solid 2(13 kg), yield 88%.
δ7.55 - 7.86 (m, 15 H) 7.25 (s, 5 H) 5.96 (d, J=3.97 Hz, 2 H) 4.96
(s, 2 H)。
B, cesium carbonate (6.2 kg, 19 mol) is added to compound 2(4 kg, 9.5 mol at room temperature) tetrahydro furan
It mutters in (16 L) solution.Reaction solution stirs half an hour time at room temperature and compound 3(690 g, 9.5 mol) is added to reaction solution
In, reaction solution is warming up to 50 DEG C and stirs 18 hours.Reaction solution is cooled to depressurize after room temperature and is filtered.Filter cake uses ethyl acetate (3
L x 3) it elutes, the filtrate decompression after merging is concentrated to get crude product.Crude product chromatographs (petrol ether/ethyl acetate body using column
Product ratio=1/0-10/1) isolated yellow oily compound 4(440 g), yield 26%.
δ7.28 - 7.43 (m, 5 H) 5.89 - 5.98 (m, 1 H) 5.29 (q, J=2.50 Hz, 1 H)
5.18 (q, J=2.35 Hz, 1 H) 4.77 (s, 1 H)。
C, methanol (1.2 L) is dispersed by hydroxide palladium carbon (25 g), then by compound 4(115 g, 0.65 mol)
It is added in reaction solution, reaction is vacuumized using H2Displacement 3 times.H of the reaction solution in 50psi2Under conditions of 50 DEG C of stirrings it is 18 small
When.TLC shows raw material end of reaction.Reaction solution is depressurized and is filtered, filter cake is eluted using methanol (200 mL), the filtrate after merging
It is concentrated under reduced pressure to give crude product.Crude product obtains colorless and transparent oily compound 5(46 using water pump vacuum distillation (75-81 DEG C)
G), yield 90%.
δ4.78 (dd, J=7.94, 6.17 Hz, 1 H) 4.47 (t, J=5.95 Hz, 1 H) 3.76 (d, J=
6.62 Hz, 1 H) 3.05 - 3.20 (m, 1 H)。
Embodiment 3: step a reacts 10 hours, and step b reacts 20 hours, remaining is the same as embodiment 2.
Embodiment 4: step a reacts 20 hours, and step b reacts 10 hours, remaining is the same as embodiment 2.
Claims (4)
1. a kind of preparation method for disliking fourth cycloalkanes -3- base methanol, it is characterized in that: the following steps are included: the first step, compound 1 with
Triphenylphosphine generates compound 2 in ethyl acetate, and second step, compound 2 is with compound 3 in cesium carbonate in tetrahydrofuran
Compound 4, third step are obtained under effect, compound 4 obtains product 5 after hydroxide palladium carbon in methyl alcohol hydro-reduction, reaction
Formula is as follows:
。
2. a kind of preparation method for disliking fourth cycloalkanes -3- base methanol according to claim 1, it is characterized in that: 50 DEG C of the first step
Reaction 10-20 hours.
3. a kind of preparation method for disliking fourth cycloalkanes -3- base methanol according to claim 1, it is characterized in that: 50 DEG C of second step
Reaction 10-20 hours.
4. a kind of preparation method for disliking fourth cycloalkanes -3- base methanol according to claim 1, it is characterized in that: 50 DEG C of third step
Reaction 18 hours.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101381286A (en) * | 2007-09-07 | 2009-03-11 | 上海睿智化学研究有限公司 | Method for synthesizing triphenylphosphine onium salts and halomethyl benzyl ethers compounds |
| CN101541756A (en) * | 2006-07-24 | 2009-09-23 | 霍夫曼-拉罗奇有限公司 | Pyrazoles as glucokinase activators |
| CN106413715A (en) * | 2014-04-22 | 2017-02-15 | 林伯士艾瑞斯公司 | IRAK inhibitors and uses thereof |
| CN108314665A (en) * | 2018-04-11 | 2018-07-24 | 上海馨远医药科技有限公司 | A kind of preparation method of 3- oxetanes formic acid |
| CN109232350A (en) * | 2018-10-25 | 2019-01-18 | 辽宁东科药业有限公司 | A method of preparing N-Boc-3- pyrrolidine formaldehyde |
-
2019
- 2019-07-23 CN CN201910664444.8A patent/CN110498779A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101541756A (en) * | 2006-07-24 | 2009-09-23 | 霍夫曼-拉罗奇有限公司 | Pyrazoles as glucokinase activators |
| CN101381286A (en) * | 2007-09-07 | 2009-03-11 | 上海睿智化学研究有限公司 | Method for synthesizing triphenylphosphine onium salts and halomethyl benzyl ethers compounds |
| CN106413715A (en) * | 2014-04-22 | 2017-02-15 | 林伯士艾瑞斯公司 | IRAK inhibitors and uses thereof |
| CN108314665A (en) * | 2018-04-11 | 2018-07-24 | 上海馨远医药科技有限公司 | A kind of preparation method of 3- oxetanes formic acid |
| CN109232350A (en) * | 2018-10-25 | 2019-01-18 | 辽宁东科药业有限公司 | A method of preparing N-Boc-3- pyrrolidine formaldehyde |
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