CN113493396A - Process for preparing 3-methylenecyclobutyl derivatives - Google Patents
Process for preparing 3-methylenecyclobutyl derivatives Download PDFInfo
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- CN113493396A CN113493396A CN202010270174.5A CN202010270174A CN113493396A CN 113493396 A CN113493396 A CN 113493396A CN 202010270174 A CN202010270174 A CN 202010270174A CN 113493396 A CN113493396 A CN 113493396A
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- -1 3-methylenecyclobutyl Chemical class 0.000 title claims abstract description 13
- 238000004519 manufacturing process Methods 0.000 title description 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 19
- 238000006116 polymerization reaction Methods 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 14
- 239000003112 inhibitor Substances 0.000 claims abstract description 13
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 11
- 238000002360 preparation method Methods 0.000 claims abstract description 9
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 claims abstract description 9
- IYABWNGZIDDRAK-UHFFFAOYSA-N allene Chemical compound C=C=C IYABWNGZIDDRAK-UHFFFAOYSA-N 0.000 claims abstract description 6
- NWVVVBRKAWDGAB-UHFFFAOYSA-N p-methoxyphenol Chemical group COC1=CC=C(O)C=C1 NWVVVBRKAWDGAB-UHFFFAOYSA-N 0.000 claims description 16
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 7
- 150000001361 allenes Chemical class 0.000 claims description 5
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical group CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- 229940113088 dimethylacetamide Drugs 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 238000012216 screening Methods 0.000 abstract description 4
- 238000005516 engineering process Methods 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 8
- 238000001816 cooling Methods 0.000 description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- 230000014759 maintenance of location Effects 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 229910001220 stainless steel Inorganic materials 0.000 description 4
- 239000010935 stainless steel Substances 0.000 description 4
- 238000007599 discharging Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- ZRWMAMOBIQQJSA-UHFFFAOYSA-N 3-methylidenecyclobutane-1-carbonitrile Chemical compound C=C1CC(C#N)C1 ZRWMAMOBIQQJSA-UHFFFAOYSA-N 0.000 description 1
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 description 1
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- UWYWTAJYUHMEKV-UHFFFAOYSA-N methyl 2-methylidenecyclobutane-1-carboxylate Chemical compound COC(=O)C1CCC1=C UWYWTAJYUHMEKV-UHFFFAOYSA-N 0.000 description 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- LYBIZMNPXTXVMV-UHFFFAOYSA-N propan-2-yl prop-2-enoate Chemical compound CC(C)OC(=O)C=C LYBIZMNPXTXVMV-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C67/347—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by addition to unsaturated carbon-to-carbon bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
Abstract
The invention provides a preparation method of a 3-methylene cyclobutyl derivative, which takes a propylene derivative and propadiene as initial raw materials, adopts a continuous flow chemical technology, and solves the problem that a reaction channel is blocked by polymerization of the propylene derivative while ensuring the conversion rate of a product by screening process conditions such as a polymerization inhibitor, a reaction solvent and the like.
Description
Technical Field
The invention relates to the field of organic chemical synthesis, in particular to a preparation method of a 3-methylene cyclobutyl derivative.
Background
3-methylene cyclobutyl derivatives are widely used as pharmaceutical intermediates in the synthesis of various drug molecules.
The existing preparation of 3-methylene cyclobutyl derivatives such as 3-methylene cyclobutylcarbonitrile generally has long-time reaction (more than 30 hours) under the conditions of high temperature (200 ℃) and high pressure (3-4MPa), needs to use an autoclave and has high requirements on equipment; and the propylene derivative is easy to polymerize to cause reaction runaway, a long-time high-temperature reaction has great safety risk, and a large amount of polymer is attached to an autoclave after the reaction, so that the equipment is difficult to clean.
Disclosure of Invention
In order to solve the problems of high safety, controllability, equipment requirement and the like of the existing industrial production of the 3-methylene cyclobutyl derivatives, the invention provides a preparation method of the 3-methylene cyclobutyl derivatives on the one hand, which is characterized in that:
dissolving propylene derivative, polymerization inhibitor and propadiene in a reaction solvent, and introducing into a continuous reactor for reaction to obtain 3-methylene cyclobutyl derivative, wherein R is-CN, -C (O) OCH3、-C(O)OC2H5、-C(O)OCH(CH3)CH3。
Preferably, the polymerization inhibitor is 4-methoxyphenol or hydroquinone; the reaction solvent is dimethyl acetamide or N-methyl pyrrolidone.
More preferably, the polymerization inhibitor is 4-methoxyphenol and the reaction solvent is N-methylpyrrolidone.
Preferably, the reaction temperature is 200-280 ℃.
Preferably, the molar ratio of polymerization inhibitor to allene is greater than or equal to 0.1%, more preferably between 0.1% and 2.9%.
Preferably, the molar ratio of the propylene derivative to the allene is 1.5 to 3.5:1, more preferably 3.5: 1.
Preferably, the reaction residence time in the continuous reactor is 11-110 minutes, and the reaction pressure is 2.5-5.5 MPa.
The invention does not limit the type, material and the like of the continuous reactor. Any continuous reactor that can be used to carry out the solution according to the invention is possible.
Preferably, the continuous reactor is a microchannel reactor, a tubular reactor or a plate reactor.
On one hand, the invention adopts continuous flow chemical technology, and uses a continuous reactor to ensure that the whole reaction process is safe and controllable; on the other hand, the invention solves the problem that the reaction channel is blocked by the polymerization of the propylene derivative while ensuring the conversion rate of the product by screening the process conditions of the polymerization inhibitor, the reaction solvent and the like.
Detailed Description
Example 13 preparation of methylenecyclobutylcarbonitrile
Dissolving acrylonitrile (3.71kg, 69.9mol, 3.5eq.) and 4-methoxyphenol (24.8g, 0.20mol, 0.01eq.) in N-methylpyrrolidone (8800g), cooling to 10-15 ℃, introducing propadiene (800g, 20.0mol, 1.0eq.), and keeping the temperature at about 10 ℃.
The temperature of heat conducting oil of a continuous reactor (a stainless steel tube reactor with the inner diameter of 6mm and the effective volume of 380mL) is set to be 250 ℃, the prepared solution enters the continuous reactor at the speed of 5.43mL/min by using a plunger pump, the system pressure is 5.5MPa, the retention time is 70 minutes, and the solution is cooled by water and then discharged. The reaction mixture was distilled through a bayonet column (20cm), the fractions were combined, water (1600mL) and MTBE (8000mL) were added, the mixture was stirred, the mixture was separated, the organic phase was washed twice with water (1600mL), and the mixture was desolventized to give 1414g of a colorless liquid.1H NMR(400MHz,CDCl3) δ (ppm)3.11-3.12(d,5H, J ═ 1.84),4.88-4.89(t,2H, J ═ 1.4), GC: 99.7%, content: 97.7 percent.
EXAMPLE 23 preparation of methyl methylenecyclobutane-1-carboxylate
Methyl acrylate (6.02kg, 70.0mol, 3.5eq.), 4-methoxyphenol (124g, 1.0mol, 0.05eq.) were dissolved in N-methylpyrrolidone (8800g), cooled to 10-15 deg.C, charged with propadiene (800g, 20.0mol, 1.0eq.), and held at about 10 deg.C.
Setting the temperature of heat conducting oil of a continuous reactor (a stainless steel tube reactor with the inner diameter of 6mm and the effective volume of 300mL) at 250 ℃, enabling the prepared solution to enter the continuous reactor at the speed of 4.29mL/min by using a plunger pump, enabling the system pressure to be 5.5MPa and the retention time to be 70 minutes, and discharging after water cooling. The reaction mixture was distilled through a bayonet column (20cm), the fractions were combined, water (1600mL) and MTBE (8000mL) were added, the mixture was stirred, the mixture was separated by stirring, and the organic phase was washed twice with water (1600mL) and then desolventized to give 1765g of a pale yellow oil.
EXAMPLE 33 preparation of Ethyl-methylenecyclobutane-1-carboxylate
Dissolving ethyl acrylate (3.0kg, 30.0mol, 1.5eq.), 4-methoxyphenol (124g, 1.0mol, 0.05eq.) in N-methylpyrrolidone (8800g), cooling to 10-15 ℃, introducing propadiene (800g, 20.0mol, 1.0eq.), and keeping the temperature at about 10 ℃.
Setting the temperature of heat conducting oil of a continuous reactor (a stainless steel tube reactor with the inner diameter of 6mm and the effective volume of 300mL) at 250 ℃, enabling the prepared solution to enter the continuous reactor at the speed of 5mL/min by using a plunger pump, enabling the system pressure to be 5.5MPa and the retention time to be 60 minutes, cooling by water, and discharging. The reaction mixture was distilled through a bayonet column (20cm), the fractions were combined, water (1600mL) and MTBE (8000mL) were added, the mixture was stirred, the mixture was separated by stirring, and the organic phase was washed twice with water (1600mL) and then desolventized to give 1820g of a pale yellow oil.
EXAMPLE 43 preparation of isopropyl methylenecyclobutane-1-carboxylate
Isopropyl acrylate (4.56kg, 40.0mol, 2.0eq.), 4-methoxyphenol (124g, 1.0mol, 0.05eq.) were dissolved in dimethylacetamide (8000g), cooled to 10-15 ℃, allene (800g, 20.0mol, 1.0eq.) was added, and the temperature was maintained at about 10 ℃.
Setting the temperature of heat conducting oil of a continuous reactor (a stainless steel tube reactor with the inner diameter of 6mm and the effective volume of 300mL) at 250 ℃, enabling the prepared solution to enter the continuous reactor at the speed of 3mL/min by using a plunger pump, enabling the system pressure to be 5.5MPa and the retention time to be 100 minutes, cooling by water, and discharging. The reaction mixture was distilled through a bayonet column (20cm), the fractions were combined, water (1600mL) and MTBE (8000mL) were added, the mixture was separated by stirring, and the organic phase was washed twice with water (1600mL) and then exsolved to give 1941g of a yellow oil.
Test example 1 polymerization inhibitor and reaction solvent screening test
The polymerization inhibitor and the reaction solvent were screened with reference to the production procedure of example 1, and the results are shown in Table 1.
TABLE 1
Therefore, the invention solves the problem that the reaction channel is blocked by the polymerization of the propylene derivative while ensuring the product conversion rate by screening the process conditions of the polymerization inhibitor, the reaction solvent and the like.
Claims (10)
1. A process for the preparation of a 3-methylenecyclobutyl derivative, characterized in that:
dissolving propylene derivative, polymerization inhibitor and propadiene in a reaction solvent, and introducing into a continuous reactor for reaction to obtain 3-methylene cyclobutyl derivative, wherein R is-CN, -C (O) OCH3、-C(O)OC2H5or-C (O) OCH (CH)3)CH3。
2. The method of claim 1, wherein: the polymerization inhibitor is 4-methoxyphenol or hydroquinone.
3. The method of claim 1, wherein: the reaction solvent is dimethyl acetamide or N-methyl pyrrolidone.
4. The method of claim 1, wherein: the polymerization inhibitor is 4-methoxyphenol, and the reaction solvent is N-methylpyrrolidone.
5. The method of claim 1, wherein: the reaction temperature is 200-280 ℃.
6. The method of claim 1, wherein: the molar ratio of the polymerization inhibitor to the allene is greater than or equal to 0.1%.
7. The method of claim 1, wherein: the molar ratio of the propylene derivative to the allene is 1.5-3.5: 1.
8. The method of claim 1, wherein: the reaction residence time in the continuous reactor is 11 to 110 minutes.
9. The method of claim 1, wherein: the reaction pressure is 2.5-5.5 MPa.
10. The method of claim 1, wherein: the continuous reactor is a microchannel reactor, a tubular reactor or a plate reactor.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010270174.5A CN113493396A (en) | 2020-04-08 | 2020-04-08 | Process for preparing 3-methylenecyclobutyl derivatives |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202010270174.5A CN113493396A (en) | 2020-04-08 | 2020-04-08 | Process for preparing 3-methylenecyclobutyl derivatives |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2914541A (en) * | 1955-09-02 | 1959-11-24 | Du Pont | 3-methylene-cyclobutanes |
| RU2174505C1 (en) * | 2000-02-18 | 2001-10-10 | Открытое акционерное общество "Всероссийский научно-исследовательский институт органического синтеза" | Method of preparing functionally substituted methylene cyclobutane |
| RU2186764C1 (en) * | 2000-11-21 | 2002-08-10 | Открытое акционерное общество "Всероссийский научно-исследовательский институт органического синтеза" | Method of synthesis of methylenecyclobutane carbonitrile |
-
2020
- 2020-04-08 CN CN202010270174.5A patent/CN113493396A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2914541A (en) * | 1955-09-02 | 1959-11-24 | Du Pont | 3-methylene-cyclobutanes |
| RU2174505C1 (en) * | 2000-02-18 | 2001-10-10 | Открытое акционерное общество "Всероссийский научно-исследовательский институт органического синтеза" | Method of preparing functionally substituted methylene cyclobutane |
| RU2186764C1 (en) * | 2000-11-21 | 2002-08-10 | Открытое акционерное общество "Всероссийский научно-исследовательский институт органического синтеза" | Method of synthesis of methylenecyclobutane carbonitrile |
Non-Patent Citations (1)
| Title |
|---|
| GIL-AV, EMANUEL，SHABTAI, JOSEPH: "Synthesis and Reactions of 3-Methylcyclobutene", 《JOURNAL OF ORGANIC CHEMISTRY》, vol. 29, no. 2, pages 260 * |
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