CN102101837A - Preparation method of cis-hexahydroisoindoline - Google Patents

Abstract

The invention discloses a preparation method of cis-hexahydroisoindoline, which comprises the following steps: enabling maleic anhydride and 1,3-butadiene, which are used as raw materials, to be subjected to Diels-Alder reaction to obtain cis-1,2,3,6-tetrahydrophthalic anhydride (I); carrying out Pb/C hydrogenation on the product I to obtain cis-cyclohexanedicarboxylic anhydride (II); reacting the product II with carbamide to obtain cis-hexahydrophthalimide (III); and reducing the product III with lithium aluminum hydride in anhydrous tetrahydrofuran to obtain the target product cis-hexahydroisoindoline. The Mitiglinide calcium preparation method disclosed by the invention can save the raw material cis-hexahydroisoindoline, and has high chiral degree of separation.

Description

A kind of preparation method of suitable-six hydrogen isoindole

Technical field

The present invention relates to a kind of preparation method of suitable-six hydrogen isoindole.

Background technology

Suitable-six hydrogen isoindole are important intermediate of S 21403, and its derivative also can be used to prepare other medicine or agrochemistry product.Suitable-six hydrogen isoindole generally are to be raw material with maleic anhydride and 1,3-butadiene earlier, adopt classical Di Ersi-Alder (Diels-Alder) reaction, obtain cis-1,2,3, the 6-Tetra Hydro Phthalic Anhydride, and then obtain suitable-1,2,3 with ammonia gas react, the 6-tetrahydric phthalimide, adopt the raney ni catalysis hydrogenation then, ethylene linkage on elder generation's reduction phenyl ring and the carbonyl on one of them acid amides, a remaining carbonyl adopts lithium aluminum hydride to reduce again.With Raney's nickel suitable-tetrahydric phthalimide is carried out the pressure that shortening needs 12 MPa, reaction conditions requires high, and is not easy to operate, and yield is on the low side in reduction process, and reduction not exclusively.

Summary of the invention

Technical problem to be solved by this invention provides the preparation method of a kind of reaction conditions temperature, suitable-six hydrogen isoindole that yield easy to operate is high.

For solving the problems of the technologies described above, the technical solution used in the present invention is a kind of preparation method of suitable-six hydrogen isoindole, and reaction equation is as follows:

Synthesis step is as follows:

Step 1, suitable-1,2,3,6-Tetra Hydro Phthalic Anhydride synthetic

The maleic anhydride adding is filled in the reactor of dry benzene, and under the heated and stirred, at the uniform velocity (0.6 ~ 0.8 L/min) feeds 1, after 3-divinyl, temperature of reaction reach 50 ℃, reheat 3～5 min, stop heating then, continue to feed 1,3-butadiene, reaction 3.0～3.5 h, GC detect the raw material maleic anhydride and disappear stopped reaction, 0 ~ 5 ℃ leaves standstill 10～12 h crystallizatioies, suction filtration, sherwood oil flushing, dry constant weight, yield for≤60 ℃: 94～97%;

Synthesizing of step 2, cis cyclohexyl dicarboxylic acid acid anhydride

With suitable-1,2,3, the 6-Tetra Hydro Phthalic Anhydride is dissolved in methyl alcohol, adds 10%Pd/C, vacuumizes earlier, use hydrogen exchange then 3 times, feed hydrogen, normal pressure hydrogenation reaction 20 ~ 25 hours, the suction filtration reaction solution, filtrate decompression concentrates, recrystallization in gained residual solid-5 ~ 0 ℃ acetone, wherein suitable-1,2,3, the mass ratio of 6-Tetra Hydro Phthalic Anhydride and 10%Pd/C is 1:0.15 ~ 0.20;

Synthesizing of step 3, suitable-hexahydrophthalic phthalimide

In the reactor, add cis cyclohexyl dicarboxylic acid acid anhydride and urea, by the speed intensification of 1 ~ 2 ℃/5 min, after treating that solid melts, begin to stir, continue to be warming up to backflow, keep slowly refluxing 1 ~ 2 h, LC-Ms detects raw material cis cyclohexyl dicarboxylic acid acid anhydride and disappears, and in the reaction solution frozen water of falling people, leaves standstill crystallization, suction filtration, the frozen water washing, the solid oven dry gets white crystal; Wherein the mol ratio of cis cyclohexyl dicarboxylic acid acid anhydride and urea is 2:1.0 ~ 1.2;

Synthesizing of step 4, suitable-six hydrogen isoindole

Tetrahydrochysene lithium aluminium joins in the anhydrous tetrahydro furan, cooling, 0 ~ 5 ℃ of adding of controlled temperature is suitable-hexahydrophthalic phthalimide, finish, be warmed up to 20 ~ 25 ℃, keep this temperature to stir 15 ~ 20 min, and then be heated to back flow reaction 24 ~ 30 h, LC-Ms detects raw material, and suitable-hexahydrophthalic phthalimide disappears, be cooled to 0 ~ 5 ℃, and keep this temperature to add water, add the aqueous sodium hydroxide solution of 15wt.% again, suction filtration, filter cake washs with tetrahydrofuran (THF), steams except that behind the tetrahydrofuran (THF), collects cut 60 ~ 65 ℃/665 ~ 670 Pa, get suitable-six hydrogen isoindole of target product, the mol ratio of wherein suitable-hexahydrophthalic phthalimide and tetrahydrochysene lithium aluminium is 1:2.5 ~ 4.0.

Beneficial effect: the preparation method of a kind of reaction conditions temperature of the present invention, suitable-six hydrogen isoindole that yield easy to operate is high.

Embodiment

Further specify the present invention by following examples, but not as limitation of the present invention.

Embodiment one

Step 1, suitable-1,2,3,6-Tetra Hydro Phthalic Anhydride synthetic

Maleic anhydride (98.0 g, 1.000 mol) adding is filled in the reactor of dry benzene (250 mL), under the heated and stirred, at the uniform velocity (0.6 ~ 0.8 L/min) feeds 1,3-butadiene, after temperature of reaction reaches 50 ℃, reheat 3 min stop heating then, continue to feed 1, the 3-divinyl reacts 3.5 h, and GC detects the raw material maleic anhydride and disappears, stopped reaction, 0 ~ 5 ℃ leaves standstill 12 h crystallizatioies, suction filtration, the sherwood oil flushing is dried constant weight, yield for≤60 ℃: 96.7%;

Synthesizing of step 2, cis cyclohexyl dicarboxylic acid acid anhydride

With suitable-1,2,3,6-Tetra Hydro Phthalic Anhydride (178.3 g, 1.173 mol) be dissolved in methyl alcohol (2000 mL), add 10%Pd/C(35.6 g), vacuumize earlier, use hydrogen exchange then 3 times, feed hydrogen, normal pressure hydrogenation reaction 22 hours, suction filtration reaction solution, filtrate decompression concentrates, recrystallization in gained residual solid-5 ~ 0 ℃ acetone;

Synthesizing of step 3, suitable-hexahydrophthalic phthalimide

In the reactor, add cis cyclohexyl dicarboxylic acid acid anhydride (83.1 g, 0.600 mol) and urea (21.6 g, 0.360 mol), heat up by the speed of 1 ~ 2 ℃/5 min, treat that solid melts after, begin to stir, continue to be warming up to backflow, keep slowly refluxing 1.5 h, LC-Ms detects raw material cis cyclohexyl dicarboxylic acid acid anhydride and disappears, and in the reaction solution frozen water of falling people, leaves standstill crystallization, suction filtration, frozen water washing, solid oven dry, get white crystal, yield: 85.9%;

Synthesizing of step 4, suitable-six hydrogen isoindole

Tetrahydrochysene lithium aluminium (416.9 g, 12.090 mol) join in the anhydrous tetrahydro furan (5000 mL), cooling, 0 ~ 5 ℃ of adding of controlled temperature is suitable-hexahydrophthalic phthalimide (47.4 g, 0.310 mol), finish, be warmed up to 20 ~ 25 ℃, keep this temperature to stir 20 min, and then be heated to back flow reaction 30 h, LC-Ms detects raw material, and suitable-hexahydrophthalic phthalimide disappears, be cooled to 0 ~ 5 ℃, and keep this temperature to add water (100 mL), add the aqueous sodium hydroxide solution (50 mL) of 15wt.% again, suction filtration, filter cake steams except that behind the tetrahydrofuran (THF) with tetrahydrofuran (THF) (50 mL * 3) washing, collects cut 60 ~ 65 ℃/665 ~ 670 Pa, get suitable-six hydrogen isoindole of target product, yield: 73.4%.

Claims (2)

1. the preparation method of suitable-six hydrogen isoindole may further comprise the steps:

Step 1, suitable-1,2,3,6-Tetra Hydro Phthalic Anhydride synthetic

Synthesizing of step 2, cis cyclohexyl dicarboxylic acid acid anhydride

Synthesizing of step 3, suitable-hexahydrophthalic phthalimide

Synthesizing of step 4, suitable-six hydrogen isoindole

The reaction equation of above step is as follows:

。

2. the preparation method of a kind of suitable-six hydrogen isoindole according to claim 1 is characterized in that, step is as follows:

Step 1, suitable-1,2,3,6-Tetra Hydro Phthalic Anhydride synthetic

The maleic anhydride adding is filled in the reactor of dry benzene, and under the heated and stirred, at the uniform velocity (0.6 ~ 0.8 L/min) feeds 1, after 3-divinyl, temperature of reaction reach 50 ℃, reheat 3～5 min, stop heating then, continue to feed 1,3-butadiene, reaction 3.0～3.5 h, GC detect the raw material maleic anhydride and disappear stopped reaction, 0 ~ 5 ℃ leaves standstill 10～12 h crystallizatioies, suction filtration, the sherwood oil flushing is dried constant weight for≤60 ℃;

Synthesizing of step 2, cis cyclohexyl dicarboxylic acid acid anhydride

With suitable-1,2,3, the 6-Tetra Hydro Phthalic Anhydride is dissolved in methyl alcohol, adds 10%Pd/C, vacuumizes earlier, use hydrogen exchange then 3 times, feed hydrogen, normal pressure hydrogenation reaction 20 ~ 25 hours, the suction filtration reaction solution, filtrate decompression concentrates, recrystallization in gained residual solid-5 ~ 0 ℃ acetone, wherein suitable-1,2,3, the mass ratio of 6-Tetra Hydro Phthalic Anhydride and 10%Pd/C is 1:0.15 ~ 0.20;

Synthesizing of step 3, suitable-hexahydrophthalic phthalimide

In the reactor, add cis cyclohexyl dicarboxylic acid acid anhydride and urea, by the speed intensification of 1 ~ 2 ℃/5 min, after treating that solid melts, begin to stir, continue to be warming up to backflow, keep slowly refluxing 1 ~ 2 h, LC-Ms detects raw material cis cyclohexyl dicarboxylic acid acid anhydride and disappears, and in the reaction solution frozen water of falling people, leaves standstill crystallization, suction filtration, the frozen water washing, the solid oven dry gets white crystal; Wherein the mol ratio of cis cyclohexyl dicarboxylic acid acid anhydride and urea is 2:1.0 ~ 1.2;

Synthesizing of step 4, suitable-six hydrogen isoindole

Tetrahydrochysene lithium aluminium joins in the anhydrous tetrahydro furan, cooling, 0 ~ 5 ℃ of adding of controlled temperature is suitable-hexahydrophthalic phthalimide, finish, be warmed up to 20 ~ 25 ℃, keep this temperature to stir 15 ~ 20 min, and then be heated to back flow reaction 24 ~ 30 h, LC-Ms detects raw material, and suitable-hexahydrophthalic phthalimide disappears, be cooled to 0 ~ 5 ℃, and keep this temperature to add water, add the aqueous sodium hydroxide solution of 15wt.% again, suction filtration, filter cake washs with tetrahydrofuran (THF), steams except that behind the tetrahydrofuran (THF), collects cut 60 ~ 65 ℃/665 ~ 670 Pa, get suitable-six hydrogen isoindole of target product, the mol ratio of wherein suitable-hexahydrophthalic phthalimide and tetrahydrochysene lithium aluminium is 1:2.5 ~ 4.0.