Method for synthesizing tetrahydroisoquinoline thiazolidine

Abstract

The present invention relates to a method for synthesizing tetrahydroisoquinoline thiazolidine, which can be conducted under a relatively mild reaction condition and can rapidly synthesize tetrahydroisoquinoline thiazolidine.

Claims

1. A method for synthesizing tetrahydroisoquinoline thiazolidine of formula (III) and formula (IV): ##STR00015## ##STR00016## comprising reacting, at a temperature between 20 C. and 100 C. in a solvent, a compound of Formula (II) and a compound of Formula (I): ##STR00017## ##STR00018## wherein, R.sub.1 is selected from the group consisting of hydrogen, halogen, an alkyl group, and an alkoxy group; R.sub.2 is selected from the group consisting of an alkoxy group, an aryloxy group, and N(OMe)Me, wherein Me is a methyl group; and the solvent is selected from the group consisting of tetrahydrofuran (THF), ethyl acetate (EtOAc), ethanol, dichloromethane (DCM), acetone, and acetonitrile.

2. The method for synthesizing tetrahydroisoquinoline thiazolidine of claim 1, wherein a ratio of the compound of Formula (III) to the compound of Formula (IV) is between 2:1 and 4:1.

3. The method for synthesizing tetrahydroisoquinoline thiazolidine of claim 1, wherein the compound of Formula (I) and the compound of Formula (II) are reacted in a ratio of 1:1.

4. The method for synthesizing tetrahydroisoquinoline thiazolidine of claim 1, further comprising an acidic additive.

5. The method for synthesizing tetrahydroisoquinoline thiazolidine of claim 4, wherein the acidic additive is acetic acid (AcOH).

6. The method for synthesizing tetrahydroisoquinoline thiazolidine of claim 1, wherein the method is carried out under reflux.

7. The method for synthesizing tetrahydroisoquinoline thiazolidine of claim 1, wherein the method has a reaction time between 30 minutes and 3 hours.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) None.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

(2) The detailed description and technical content of the present invention are illustrated hereafter in connection with experiments:

(3) The present invention provides a method for synthesizing tetrahydroisoquinoline thiazolidine, in which a compound 1a and a compound 1b are reacted at a temperature between 20 C. and 100 C. in a solvent, wherein the compound 1a comprises a structure of Formula (I), and the compound 1b comprises a structure of Formula (II).

(4) ##STR00007##

(5) ##STR00008##

(6) In the present invention, R.sub.1 is selected from the group consisting of hydrogen, halogen, an alkyl group, and an alkoxy group; and R.sub.2 is selected from the group consisting of an alkoxy group, an aryloxy group, and N(OMe)Me, wherein Me is a methyl group. For example, the halogen may be fluorine, chlorine, bromine, iodine and the like; the alkyl group may be an alkyl group comprising 1 to 2 carbon atoms, such as methyl, ethyl and the like; and the alkoxy group may be an alkoxy group comprising 1 to 2 carbon atoms, such as a methoxy group (OCH3), an ethoxy group (OCH2CH3) and the like.

(7) In the present invention, the solvent is selected from the group consisting of tetrahydrofuran (THF), ethyl acetate (EtOAc), acetone, ethanol, dichloromethane (DCM), acetone, and acetonitrile.

(8) In an embodiment of the present invention, the compound 1a and the compound 1b are reacted to form a compound 1c of Formula (III) and a compound 1d of Formula (IV), wherein the compound 1c and the compound 1d are diastereomers.

(9) ##STR00009##

(10) ##STR00010##

(11) In an embodiment of the present invention, the ratio of the compound 1c of Formula (III) to the compound 1d of Formula (IV) is approximately between 2:1 and 4:1. For example, in an embodiment the ratio of the compound 1c of Formula (III) to the compound 1d of Formula (IV) is about 3:1.

(12) In an embodiment of the present invention, the compound 1a and the compound 1b are reacted with an equivalent ratio of 1:1.

(13) During the synthesis process of the present invention, an acidic additive is further added to shorten the reaction time and increase the productivity. A specific example of the acidic additive is acetic acid (AcOH).

(14) In an embodiment of the present invention, the reaction can be carried out under reflux to maintain a certain reaction temperature. However, the present invention is not limited to this, as long as the reaction is carried out at a temperature between 20 C. and 100 C. In other embodiments, the reaction can also be carried out at room temperature while a good productivity can still be obtained.

(15) In an embodiment of the present invention, the time required for completing the synthesis may be between 30 minutes and 3 hours, between 1 hour and 2 hours, or even about 1 hour to complete the synthesis of tetrahydroisoquinoline thiazolidine.

(16) The synthesis steps of the present invention will be illustrated in details in connection with examples hereafter.

Experiment Example 1

(17) Firstly, a compound 1a (which is an isoquinoline) and a compound 1b (which is a ,-unsaturated ester compound) were used as starting materials, and tetrahydrofuran (THF) was used as a solvent, to conduct a reaction at room temperature (rt).

(18) ##STR00011##

(19) During the reaction process, by monitoring the reaction extent via paper chromatography and thin layer chromatography (TLC), it was found that it was required to take about 48 hours for the compound 1b to complete the reaction, with a yield of 52%.

(20) In order to shorten the reaction time and improve the productivity, different kinds of additives were added during the reaction process, and the reaction time, the productivity and the product ratio of the compound 1c to the compound 1d were observed as shown in Table 1.

(21) TABLE-US-00001 TABLE 1 Additive Reaction Time Productivity Compound 1c: Group (equivalent) (hour) (%) Compound 1d 1 NA 48 52 3:1 2 K.sub.2CO.sub.3 (1.0) 48 50 3:1 3 DMAP (1.0) 48 53 3:1 4 TEA (1.0) 1 50 3:1 5 AcOH (1.0) 1 50 3:1 6 AcOH (2.0) 1 57 3:1 7 AcOH (3.0) 1 69 3:1 8 HCOOH (3.0) 1 60 3:1

(22) As can be seen from Table 1, the addition of acidic additives such as formic acid (HCOOH) and acetic acid (AcOH) can shorten the reaction time to 1 hour, and especially after the addition of acetic acid (AcOH), not only the reaction time was shortened, but also the productivity was increased to 69%. However, the ratio of compound 1c to compound 1d was maintained at a ratio of about 3:1, without being affected by the types of additives used in Table 1.

Experiment Example 2

(23) In this experiment example, a synthesis reaction was conducted by using the compound 1a and the compound 1b as starting materials in different solvents as shown in Table 2 below, and 3 equivalents of acetic acid (AcOH) was added as an additive. The aforementioned reaction was carried out in the same manner as in the Experimental Example 1 and at room temperature (rt), wherein the phrase room temperature (rt) is defined as a temperature between 25 C. and 28 C.

(24) ##STR00012##

(25) In this experimental example, the productivity and the ratio of the compound 1c to the compound 1d after addition of different types of solvents were observed, and the results were shown in Table 2 below.

(26) TABLE-US-00002 TABLE 2 Productivity Compound 1c: Group Solvent (%) Compound 1d 1 tetrahydrofuran 69 3:1 2 ethyl acetate 70 3:1 3 ethanol 62 3:1 4 dichloromethane 67 3:1 5 acetone 55 3:1 6 acetonitrile 50 3:1

(27) The productivity was 63% to 70% when the solvent was ethyl acetate (EtOAc), ethanol (EtOH), or dichloromethane (DCM). When the reaction was carried out in acetonitrile, the productivity was slightly reduced to 50%, which is lower than those using tetrahydrofuran (THF) as the solvent.

(28) In the Experimental Example 2, it was also observed that the ratio of compound 1c to compound 1d was maintained at about 3:1, without being influenced by the types of the solvents used in Table 2.

Experiment Example 3

(29) In this experimental example, the compound 1a and the compound 1b were used as starting materials, ethyl acetate (EtOAc) was used as a solvent, and 3 equivalents of acetic acid (AcOH) was added as an additive. The reaction was carried out at different temperatures.

(30) ##STR00013##

(31) After the aforementioned reaction, the productivity and the ratio of compound 1c to compound 1d were shown in Table 3 below.

(32) TABLE-US-00003 TABLE 3 Temperature Time Productivity Compound 1c: Group ( C.) (hour) (%) Compound 1d 1 rt 1 70 3:1 2 reflux 1 85 3:1 3 reflux 2 86 3:1

(33) As can be seen from Table 3 that, a good productivity (70%) had been achieved after a 1-hour reaction at room temperature (rt); and when reflux was used, the productivity was increased to 85% after the 1-hour reaction, and when the reaction time was increased to 2 hours under the same conditions, the productivity was 86%. However, in the Experiment Example 3, the ratio of compound 1c to compound 1d was also maintained at a ratio of about 3:1, without being affected by the temperature. The phrase room temperature is defined herein as a temperature between 25 C. and 28 C.; and the phrase reflux is defined as a temperature between 70 C. and 90 C.

Experiment Example 4

(34) The reaction conditions in Experimental Example 4 were approximately the same as those in Experimental Example 3. However, in Experimental Example 4, the ratio of the two starting materials was changed and it was observed whether or not the productivity could thus be improved as shown in Table 4.

(35) TABLE-US-00004 TABLE 4 Compound 1a Compound 1b Productivity Compound 1c: Group (equivalent) (equivalent) (%) Compound 1d 1 1.0 1.0 85 3:1 2 1.0 1.5 82 3:1 3 1.0 2 80 3:1 4 1.0 4 60 3:1

(36) When the equivalent of the compound 1b was slightly increased to 1.5 equivalents, the compound 1a was still remained and the productivity was not increased. The same result was obtained when the equivalent of the compound 1b was increased to 2 or 4 equivalents: the compound 1a still could not react completely and the productivity could not be improved.

(37) In view of the above, in this experiment example, a better productivity (85%) was obtained when the compound 1a and the compound 1b were reacted with 1:1 equivalent as starting materials.

Experiment Example 5

(38) The reaction conditions in the Experimental Example 5 were approximately the same as those in the Experimental Example 4, wherein 1 equivalent of the compound 1a and 1 equivalent of the compound 1b were used as starting materials, the solvent was ethyl acetate (EtOAc), 3 equivalents of acetic acid (AcOH) was added as an additive, and the reaction was heated under reflux for one hour. The difference from the Experimental Example 4 was that the Experimental Example 5 was conducted by reacting the compound 1a comprising a different substituent group R.sub.1 and the compound 1b having a different substituent group R.sub.2.

(39) ##STR00014##

(40) With respect to the substituent groups R.sub.1 and R.sub.2, the productivity, and the ratio of the compound 1c to the compound 1d, the results were as shown in Table 5 below.

(41) TABLE-US-00005 TABLE 5 Productivity Compound 1c: Group R.sub.1 R.sub.2 1c (%) Compound 1d 1 H OMe 212a 85 3.6:1 2 9-Cl OMe 212b 79 2.5:1 3 8-Br OMe 212c 83 2.5:1 4 8-OMe OMe 212d 63 2.5:1 5 8,9-OMe OMe 212e 87 3.5:1 6 H OEt 212f 83 3:1 7 9-OMe OEt 212g 67 3:1 8 Br OEt 212h 87 2.5:1 9 9-F OEt 212i 81 3.5:1 10 9-Me OEt 212j 84 3:1 11 H OBn 212k 81 4:1 12 7-Cl OBn 2121 80 3.7:1 13 9-Cl OBn 212m 79 4:1 14 8-OMe OBn 212n 70 4:1 15 H N(OMe)Me 212o 70 3.4:1 16 7-F N(OMe)Me 212p 61 3:1 17 9-Cl N(OMe)Me 212q 60 3:1

(42) The reaction tests were carried out respectively by using the eighth and the ninth carbon atoms on the structure of the compound 1a as electron-withdrawing substituent groups, and the generated corresponding compounds 1c were respectively named as 212b and 212c, with productivities of respectively 79% (group 2) and 83% (group 3). However, when the eighth carbon atom on the structure of the compound 1a was a methoxyl group (OMe), the reactivity was slightly poor when the compound 1c (named as 212d) was generated, and the productivity was decreased to 63% (group 4). Additionally, the compound 1c named as 212e was also successfully obtained with a productivity of 87% when the compound 1a bis-substituted at the eighth and the ninth carbon atoms with methoxy groups was used for reaction (group 5).

(43) When the compound 1b comprising a substituent group R.sub.2 of OEt (ethoxyl group) was reacted with the compound 1a comprising different substituent groups, it was found that when the substituent group R.sub.1 of the compound 1a was halogen, the compound 1c in expectation (named as 212h and 212i) were generated with productivities of 87% (group 8) and 81% (group 9), respectively; when the R.sub.1 was changed from a halogen substituent group to a methoxyl group, the productivity was decreased to 67%, and thus when a methyl group being also an electron-donating group was used, the compound 1c named as 212j with a productivity of 84% (group 10) was obtained.

(44) Substantially, the compound 1b comprising the substituent group R.sub.2 of OBn (aryloxy group) was reacted with the compound 1a comprising different types of substituent groups. When the reaction was carried out by using the compound 1a substituted with halogen at the eight and the ninth carbon, the compounds 1c respectively named as 2121 and 212m were obtained with the productivity performance of about 80% (group 12 and group 13), and when the substituent group of the compound 1a was the methoxy group, the productivity was slightly lower as compared with the aforementioned other substituent groups.

(45) Finally, the compound 1b comprising the substituent group R.sub.2 of N(OMe)Me was reacted with the compound 1a comprising different substituent groups, such that the generated corresponding thiazolidine compounds of compound 1c had a slightly lower productivity of 70-60% (named as 212o -212q, for groups 15 to 17).

(46) With respect to each of the different thiazolidine compounds synthesized in this experimental example, the diastereoselectivity ratio of the compound 1c in expectation to the compound 1d was 3:1, and the ratio was not changed due to changing of substituent groups of the compounds 1a and 1b. However, a good productivity was obtained regardless of whether there was an electron withdrawing group or an electron donating group on the molecular structure of the compound 1a, except when the substituent group was the methoxy group.

(47) In view of the above, as compared with the prior art which obtained thiazolidine compounds with a satisfactory yield only in a strict environment or after a long time is spent, the method provided by the present invention not only has milder synthesis conditions, simple and fast synthesis steps, but also has great stereoselectivity and productivity, thereby being capable of lowering the technical threshold and cost of synthesis, and meeting the green chemical concept advocated currently.