Preparation method of 3-oxocyclobutanecarboxylic acid

Abstract

The invention discloses a preparation method of 3-oxocyclobutanecarboxylic acid. The preparation method comprises the following steps: (1) preparing methyl triphenylphosphine iodide (II); (2) preparing 3-benzal cyclobutanol (III); (3) preparing methyl-benzenesulfonic acid-3-benzal cyclobutanol ester (IV); (4) preparing 3-benzal cyclobutanecarbonitrile (V); (5) preparing 3-benzal cyclobutylcarboxylic acid (VI); (6) preparing 3-oxocyclobutanecarboxylic acid (VIII). The reaction formula is shown in the description. The preparation method has the advantages that the starting raw materials are low in price; the operation can be done with conventional equipment; ozonation is performed instead of hypertoxic osmium tetroxide oxidation, so that the cost is low, and the technical operation is simple and easy to carry out.

Description

technical field

[0001] The invention relates to a preparation method of a pharmaceutical intermediate, in particular to a preparation method of 3-oxocyclobutanecarboxylic acid. Background technique

[0002] As an important pharmaceutical intermediate, 3-oxocyclobutane carboxylic acid is widely used in the synthesis of various APIs. For example, it has applications in kinase inhibitors, thrombin inhibitors and anti-tumor drugs. However, there are few reports on the synthesis method of this pharmaceutical intermediate, so it is of great significance to develop a new synthesis process.

[0003] In the literature, 3-methylenecyclobutylcarbonitrile is synthesized by the reaction of propadiene and acrylonitrile, and then oxidized to 3-oxocyclobutane carboxylic acid with osmium tetroxide and sodium periodate; another method is to use 1,3-dihalogenated methyl acetal reacts with malonic acid diester to condense and close the ring, and then decarboxylate to obtain 3-oxocyclobutane c...

Examples

Embodiment 1

[0020] A preparation method of 3-oxocyclobutane carboxylic acid (VII), comprising the steps:

[0021] (1) Preparation of methyltriphenylphosphine iodide (II)

[0022] 500 g (2.03 mol) of triphenylphosphine (I) was dissolved in 3 L of tetrahydrofuran, 432 g (3.05 mol) of methyl iodide was added dropwise to the system, and the mixture was stirred at room temperature for 12 hours to produce a large amount of white solid, which was filtered to remove excess methyl iodide. And tetrahydrofuran to obtain solid methyl triphenylphosphine iodide (II) 850g, yield 91%;

[0023] (2) Preparation of 3-benzylidenecyclobutanol (III)

[0024] Methyltriphenylphosphine iodide (II) 40.4 g (0.1 mol) was dissolved in 800 mL of toluene, and the temperature was controlled at 0 °C, and 40 mL of n-butyllithium n-hexane solution, 2.5 M (0.1 mol), dripped in 15 minutes; warmed up to room temperature and stirred for 0.5 hours; then cooled to 0 °C, and added 9.2 g (0.1 mol) of epichlorohydrin dropwise at ...

Embodiment 2

[0036] A preparation method of 3-oxocyclobutane carboxylic acid (VII), comprising the steps:

[0037] (1) Preparation of methyltriphenylphosphine iodide (II)

[0038] Dissolve 500 g (2.03 mol) of triphenylphosphine (I) in 3 L of tetrahydrofuran, add 432 g (3.05 mol) of methyl iodide to the system dropwise, and stir at room temperature for 18 hours to produce a large amount of white solids, filter to remove excess methyl iodide And tetrahydrofuran to obtain solid methyl triphenylphosphine iodide (II) 857g, yield 92%;

[0039] (2) Preparation of 3-benzylidenecyclobutanol (III)

[0040]80.8 g (0.2 mol) of methyltriphenylphosphine iodide (II) was dissolved in 1500 mL of toluene, and at -3 °C under temperature control, 96 mL of n-butyllithium in n-hexane solution, 2.5 M ( 0.24mol), dripped in 30 minutes; warmed to room temperature and stirred for 1 hour; then cooled to -3°C, and at this temperature, 18.4g (0.2mol) of epichlorohydrin was added dropwise, and stirred at -3°C for 1 h...

Embodiment 3

[0050] A preparation method of 3-oxocyclobutane carboxylic acid (VII), comprising the steps:

[0051] (1) Preparation of methyltriphenylphosphine iodide (II)

[0052] Dissolve 1000 g (4.06 mol) of triphenylphosphine (I) in 5 L of tetrahydrofuran, add 864 g (6.1 mol) of methyl iodide to the system dropwise, and stir at room temperature for 24 hours to produce a large amount of white solids, filter to remove excess methyl iodide and tetrahydrofuran to obtain solid methyl triphenylphosphine iodide (II) 1775g, yield 95%;

[0053] (2) Preparation of 3-benzylidenecyclobutanol (III)

[0054] Methyltriphenylphosphine iodide (II) 40.4g (0.1mol) was dissolved in 800mL of toluene, and the temperature was controlled at -5°C, 40mL of n-butyllithium in n-hexane solution, 2.5M ( 0.1mol), dripped in 15 minutes; warmed up to room temperature and stirred for 1 hour; then cooled to -5°C, and at this temperature, 9.2g (0.1mol) of epichlorohydrin was added dropwise, stirred at -5°C for 1 hour, ...

technical field

[0001] The invention relates to a preparation method of a pharmaceutical intermediate, in particular to a preparation method of 3-oxocyclobutanecarboxylic acid. Background technique

[0002] As an important pharmaceutical intermediate, 3-oxocyclobutane carboxylic acid is widely used in the synthesis of various APIs. For example, it has applications in kinase inhibitors, thrombin inhibitors and anti-tumor drugs. However, there are few reports on the synthesis method of this pharmaceutical intermediate, so it is of great significance to develop a new synthesis process.

[0003] In the literature, 3-methylenecyclobutylcarbonitrile is synthesized by the reaction of propadiene and acrylonitrile, and then oxidized to 3-oxocyclobutane carboxylic acid with osmium tetroxide and sodium periodate; another method is to use 1,3-dihalogenated methyl acetal reacts with malonic acid diester to condense and close the ring, and then decarboxylate to obtain 3-oxocyclobutane c...

Examples

Embodiment 1

[0020] A preparation method of 3-oxocyclobutane carboxylic acid (VII), comprising the steps:

[0021] (1) Preparation of methyltriphenylphosphine iodide (II)

[0022] 500 g (2.03 mol) of triphenylphosphine (I) was dissolved in 3 L of tetrahydrofuran, 432 g (3.05 mol) of methyl iodide was added dropwise to the system, and the mixture was stirred at room temperature for 12 hours to produce a large amount of white solid, which was filtered to remove excess methyl iodide. And tetrahydrofuran to obtain solid methyl triphenylphosphine iodide (II) 850g, yield 91%;

[0023] (2) Preparation of 3-benzylidenecyclobutanol (III)

[0024] Methyltriphenylphosphine iodide (II) 40.4 g (0.1 mol) was dissolved in 800 mL of toluene, and the temperature was controlled at 0 °C, and 40 mL of n-butyllithium n-hexane solution, 2.5 M (0.1 mol), dripped in 15 minutes; warmed up to room temperature and stirred for 0.5 hours; then cooled to 0 °C, and added 9.2 g (0.1 mol) of epichlorohydrin dropwise at ...

Embodiment 2

[0036] A preparation method of 3-oxocyclobutane carboxylic acid (VII), comprising the steps:

[0037] (1) Preparation of methyltriphenylphosphine iodide (II)

[0038] Dissolve 500 g (2.03 mol) of triphenylphosphine (I) in 3 L of tetrahydrofuran, add 432 g (3.05 mol) of methyl iodide to the system dropwise, and stir at room temperature for 18 hours to produce a large amount of white solids, filter to remove excess methyl iodide And tetrahydrofuran to obtain solid methyl triphenylphosphine iodide (II) 857g, yield 92%;

[0039] (2) Preparation of 3-benzylidenecyclobutanol (III)

[0040]80.8 g (0.2 mol) of methyltriphenylphosphine iodide (II) was dissolved in 1500 mL of toluene, and at -3 °C under temperature control, 96 mL of n-butyllithium in n-hexane solution, 2.5 M ( 0.24mol), dripped in 30 minutes; warmed to room temperature and stirred for 1 hour; then cooled to -3°C, and at this temperature, 18.4g (0.2mol) of epichlorohydrin was added dropwise, and stirred at -3°C for 1 h...

Embodiment 3

[0050] A preparation method of 3-oxocyclobutane carboxylic acid (VII), comprising the steps:

[0051] (1) Preparation of methyltriphenylphosphine iodide (II)

[0052] Dissolve 1000 g (4.06 mol) of triphenylphosphine (I) in 5 L of tetrahydrofuran, add 864 g (6.1 mol) of methyl iodide to the system dropwise, and stir at room temperature for 24 hours to produce a large amount of white solids, filter to remove excess methyl iodide and tetrahydrofuran to obtain solid methyl triphenylphosphine iodide (II) 1775g, yield 95%;

[0053] (2) Preparation of 3-benzylidenecyclobutanol (III)

[0054] Methyltriphenylphosphine iodide (II) 40.4g (0.1mol) was dissolved in 800mL of toluene, and the temperature was controlled at -5°C, 40mL of n-butyllithium in n-hexane solution, 2.5M ( 0.1mol), dripped in 15 minutes; warmed up to room temperature and stirred for 1 hour; then cooled to -5°C, and at this temperature, 9.2g (0.1mol) of epichlorohydrin was added dropwise, stirred at -5°C for 1 hour, ...

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