A chiral synthesis of 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole optical isomers

Abstract

The application discloses a chiral synthesis method of 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole optical isomers, which is composed of seven steps. 1,4-cyclohexanedione (compound of formula I) is reacted with bromine, and then reacted with thiourea to obtain 2-amino-6-oxo-4,5,6,7-tetrahydrobenzothiazole (compound of formula III); then, the compound of formula III is reacted with acetic anhydride to obtain 2-acetylamino-6-oxo-4,5,6,7-tetrahydrobenzothiazole (compound of formula IV); then, the compound of formula IV is dehydrated with R-1-phenylethylamine (compound of formula V) or S-1-phenylethylamine (compound of formula X) to generate imine, and then is reduced by sodium borohydride, benzylolysis by palladium carbon and hydrolysis to obtain 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole optical isomers. The synthesis scheme avoids the resolution step of racemates, improves the atomic economy, and the starting materials are more inexpensive and easy to obtain.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicine and chemical industry, and particularly relates to a chiral synthesis method of a key intermediate (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole of a drug for treating Parkinson's disease and an enantiomer R-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole. BACKGROUND

[0002] Pramipexole is a dopamine receptor agonist, which has high selectivity and specificity in combination with the D2 subfamily of dopamine receptors and has complete intrinsic activity, and has preferential affinity for D3 receptors. It is used to treat signs and symptoms of idiopathic Parkinson's disease, alone (without levodopa) or in combination with levodopa. Pramipexole was launched in the United States in 1997, and has been launched in many countries such as Europe, India, Japan and China.

[0003] The synthesis method of the key intermediate (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole of pramipexole described in the existing literature is to first synthesize racemic 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole, and then to separate and resolve it with L-tartaric acid to obtain (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole. For example, the synthesis of (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole is reported in the literature "Synthesis of Pramipexole Hydrochloride" (China Medical Industry Journal, 2012, 43(7)), and the synthesis route is as follows:

[0004]

[0005] The reaction route has the following disadvantages: a large amount of resolving agent is consumed to separate (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole from racemic 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole with L-tartaric acid, and only 50% of the optical isomer can be obtained in theory. If the isomer impurity is controlled below 0.5% according to the quality requirements of the raw material, only repeated purification can be carried out, and the yield will be lower, which does not meet the "atom economy" principle in green chemistry. SUMMARY

[0006] In view of the deficiencies in the prior art, the present application provides a chiral synthesis method of 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole, which can directly synthesize S-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole and its enantiomer (R)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole.

[0007] To achieve the above-mentioned purpose, the present application realizes the following technical solutions:

[0008] A chiral synthesis method of (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole, comprising the following steps:

[0009] (1) reacting 2-acetylamino-6-oxo-4,5,6,7-tetrahydrobenzothiazole compound IV with (R)-1-phenylethylamine compound V, and then reducing with sodium borohydride to generate (S)-2-acetylamino-6-(((R)-1-phenylethyl)amino)-4,5,6,7-tetrahydrobenzothiazole compound VII;

[0010]

[0011] (2) debenzylating (S)-2-acetylamino-6-(((R)-1-phenylethyl)amino)-4,5,6,7-tetrahydrobenzothiazole compound VII obtained in the above step with palladium-carbon, and then hydrolyzing to obtain (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole compound IX;

[0012]

[0013] Further, in the step (1), the solvent used in the reaction with (R)-1-phenylethylamine compound V is toluene, and the solvent used in the reduction reaction is methanol; and in the step (2), the solvent used in the reduction step is ethanol.

[0014] The application also relates to a synthesis method of 2-acetylamino-6-oxo-4,5,6,7-tetrahydrobenzothiazole compound IV, which adopts the following technical scheme:

[0015] A synthesis method of 2-acetylamino-6-oxo-4,5,6,7-tetrahydrobenzothiazole compound IV, comprising the following steps:

[0016] (1) reacting 1,4-cyclohexanedione compound I with bromine, and then reacting with thiourea to obtain 2-amino-6-oxo-4,5,6,7-tetrahydrobenzothiazole compound III;

[0017]

[0018] (2) reacting 2-amino-6-oxo-4,5,6,7-tetrahydrobenzothiazole compound III obtained in the above step with acetic anhydride to obtain 2-acetylamino-6-oxo-4,5,6,7-tetrahydrobenzothiazole compound IV;

[0019]

[0020] Further, in the step (1), the solvent used is selected from methanol, and the solvent used in the reaction with thiourea is water; and in the step (2), the solvent used is water.

[0021] Another object of the present invention is to provide a chiral synthesis method of (R)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole, which adopts the following technical scheme:

[0022] A chiral synthesis method of (R)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole comprises the following steps:

[0023] (1) 2-acetylamino-6-oxo-4,5,6,7-tetrahydrobenzothiazole compound IV and (S)-1-phenylethylamine compound X

[0024] The reaction was then reduced with sodium borohydride to generate (R)-2-acetylamino-6-(((S)-1-phenylethyl)amino)-4,5,6,7-tetrahydrobenzene

[0025] Thiazole compound XII;

[0026]

[0027] (2) The (R)-2-acetylamino-6-(((S)-1-phenylethyl)amino)-4,5,6,7-tetrahydrobenzothiazole compound XII obtained in the previous step is debenzylated with palladium on carbon and then hydrolyzed to obtain the (R)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole compound XIV;

[0028]

[0029] Furthermore, in the step (1), the solvent used in the reaction with the (S)-1-phenylethylamine compound V is toluene, and the solvent used in the reduction reaction is methanol; and in the step (2), the solvent used in the reduction step is ethanol.

[0030] Using the same reaction mechanism, (R)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole can also be synthesized. The technical scheme is as follows:

[0031] Compared with the separation and synthesis methods of 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole optical isomers reported in existing literature, the main advantages of the present invention are:

[0032] The starting material 1,4-cyclohexanedione in this case is more affordable and readily available than the starting materials p-acetylaminocyclohexanol or p-acetylaminocyclohexanone reported in existing literature. During the reduction of compound VI to compound VII or compound XI to compound XII, the inductive effect of the chiral aniline in the molecule primarily produces a single optical isomer, along with a small amount of diastereoisomers. This diastereoisomer impurity can be removed by direct recrystallization from ethanol. Subsequently, benzylic and hydrolytic reactions are performed to yield the target product as a single optical isomer with high purity.

[0033] The optical isomers of 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole obtained according to the present method have a chemical purity of more than 99.5% and an enantiomeric impurity of less than 0.2%, which meet the quality expectations of the pharmaceutical industry for key intermediates. BRIEF DESCRIPTION OF DRAWINGS

[0034] Figure 1 : HPLC detection chromatogram of chemical purity of (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole (compound of formula IX) of Example 4;

[0035] Figure 2 : HPLC detection system suitability chromatogram of chiral purity of (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole (compound of formula IX) of Example 4;

[0036] Figure 3 : HPLC detection chromatogram of chiral purity of (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole (compound of formula IX) of Example 4;

[0037] Figure 4 : HPLC detection chromatogram of chemical purity of (R)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole (compound of formula XIV) of Example 6;

[0038] Figure 5 : HPLC detection system suitability chromatogram of chiral purity of (R)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole (compound of formula XIV) of Example 6;

[0039] Figure 6 : HPLC detection chromatogram of chiral purity of (R)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole (compound of formula XIV) of Example 6. DETAILED DESCRIPTION

[0040] The above description of the present application is further illustrated by the following embodiments represented by several specific examples, but this should not be understood as limiting the scope of the above subject matter of the present application to the following specific embodiments. Any technology tested based on the above description of the present application is within the scope of the present application.

[0041] Example 1: Synthesis of compound of formula III

[0042]

[0043] In a 5000ml three-necked flask, 440g (3.9mol) of 1,4-cyclohexanedione, 1500ml of methanol were added, stirring was started, and the temperature was lowered to 5°C. 650g (4.1mol) of bromine was added dropwise within 1 hour, the temperature during the dropwise addition was 5-10°C. After the dropwise addition was completed, the temperature was kept at 5-10°C for 1 hour, and then the temperature was raised to 20°C. 360g (4.7mol) of thiourea was added to the reaction solution, 800ml of water was added, and the temperature was raised to reflux for 2 hours. The temperature was lowered to 55°C, and the white solid was filtered off. The filtrate was evaporated to remove the methanol, and then liquid alkali was added to adjust the pH value to 12.0. The temperature was lowered to 0-5°C to precipitate crystals, which were filtered off and washed with a small amount of cold water. A white solid powder was obtained, which was dried to obtain 515g of the compound of formula III, melting point 207.0-210.5°C, and the yield was 78% of moles.

[0044] Example 2: Synthesis of the compound of formula IV

[0045]

[0046] In a 5000ml three-necked flask, 440g (3.9mol) of 1,4-cyclohexanedione, 1500ml of methanol were added, stirring was started, and the temperature was lowered to 5°C. 650g (4.1mol) of bromine was added dropwise within 1 hour, the temperature during the dropwise addition was 5-10°C. After the dropwise addition was completed, the temperature was kept at 5-10°C for 1 hour, and then the temperature was raised to 20°C. 360g (4.7mol) of thiourea was added to the reaction solution, 800ml of water was added, and the temperature was raised to reflux for 2 hours. The temperature was lowered to 55°C, and the white solid was filtered off. The filtrate was evaporated to remove the methanol, and then liquid alkali was added to adjust the pH value to 12.0. The temperature was lowered to 0-5°C to precipitate crystals, which were filtered off and washed with a small amount of cold water. A white solid powder was obtained, which was dried to obtain 515g of the compound of formula III, melting point 207.0-210.5°C, and the yield was 78% of moles.

[0047] Example 3: Synthesis of the compound of formula VII

[0048]

[0049] In a 5000ml three-necked flask, 440g (3.9mol) of 1,4-cyclohexanedione, 1500ml of methanol were added, stirring was started, and the temperature was lowered to 5°C. 650g (4.1mol) of bromine was added dropwise within 1 hour, the temperature during the dropwise addition was 5-10°C. After the dropwise addition was completed, the temperature was kept at 5-10°C for 1 hour, and then the temperature was raised to 20°C. 360g (4.7mol) of thiourea was added to the reaction solution, 800ml of water was added, and the temperature was raised to reflux for 2 hours. The temperature was lowered to 55°C, and the white solid was filtered off. The filtrate was evaporated to remove the methanol, and then liquid alkali was added to adjust the pH value to 12.0. The temperature was lowered to 0-5°C to precipitate crystals, which were filtered off and washed with a small amount of cold water. A white solid powder was obtained, which was dried to obtain 515g of the compound of formula III, melting point 207.0-210.5°C, and the yield was 78% of moles.

[0050] Example 4: Synthesis of the compound of formula IX

[0051]

[0052] In a 5000 ml three necked flask, add 500 g of compound of formula IV (2.4 mol) from example 2, 315 g (2.6 mol) of S-1-phenylethylamine (compound of formula X), 3000 ml of dry toluene, reflux for 12 hours, evaporate the solvent, add 2000 ml of dry methanol, cool to 0°C, add 92 g (2.4 mol) of sodium borohydride in batches, continue to stir at 5-10°C for 12 hours, add 10% hydrochloric acid dropwise to adjust the pH of the reaction solution to 1.0, filter out the solid and wash the filter cake with an appropriate amount of methanol, mix the filter cake with 3000 ml of water, heat to 60°C to dissolve, add 1.0 g of activated carbon and stir for 1 hour to decolorize, filter, cool the filtrate to 30°C, adjust the pH to 12.0 with liquid alkali, filter to obtain a white powder, dry to obtain 703 g of white powder, recrystallize the obtained product with 3500 ml of ethanol to remove a small amount of isomers, to obtain 548 g of white powder, which is compound of formula XII, with a yield of 73%.

[0053] The obtained compound of formula IX was detected: optical detection (C=1.0, MeOH) -99.3°, purity 99.87%, enantiomer content 0.098%.

[0054] Example 5: Synthesis of compound of formula XII

[0055]

[0056] In a 5000 ml three necked flask, add 500 g of compound of formula IV (2.4 mol) from example 2, 315 g (2.6 mol) of S-1-phenylethylamine (compound of formula X), 3000 ml of dry toluene, reflux for 12 hours, evaporate the solvent, add 2000 ml of dry methanol, cool to 0°C, add 92 g (2.4 mol) of sodium borohydride in batches, continue to stir at 5-10°C for 12 hours, add 10% hydrochloric acid dropwise to adjust the pH of the reaction solution to 1.0, filter out the solid and wash the filter cake with an appropriate amount of methanol, mix the filter cake with 3000 ml of water, heat to 60°C to dissolve, add 1.0 g of activated carbon and stir for 1 hour to decolorize, filter, cool the filtrate to 30°C, adjust the pH to 12.0 with liquid alkali, filter to obtain a white powder, dry to obtain 703 g of white powder, recrystallize the obtained product with 3500 ml of ethanol to remove a small amount of isomers, to obtain 548 g of white powder, which is compound of formula XII, with a yield of 73%.

[0057] Example 6: Synthesis of compound of formula XIV

[0058]

[0059] In a high pressure reactor, add the compound of formula XII obtained in Example 5, 158 g (0.50 mol), 620 mL of anhydrous ethanol, 7.5 g of 10% Pd / C, and stir the reaction mixture at 60°C under 0.1 MPa hydrogen pressure for 7 h. Filter the solution, evaporate the filtrate under reduced pressure, add 1000 mL of water, adjust the pH to 1.0 with hydrochloric acid, extract the aqueous layer with 300 mL of dichloromethane twice, discard the organic layer, evaporate the residual small amount of dichloromethane from the aqueous layer, add 500 mL of 30% hydrochloric acid, and reflux at elevated temperature for 18 h. Cool the reaction mixture to 50°C, adjust the pH to 5.0 with liquid base, add 10 g of activated carbon, and stir for 0.5 h to decolorize. Filter the reaction mixture, adjust the pH of the filtrate to 12.0 by slowly adding liquid base at 25-30°C, filter, and dry to obtain 63 g of a white powder, which is the compound of formula XIV, in a yield of 74%.

[0060] The obtained compound of formula XIV has the following test data: optical rotation test (C = 1.0, MeOH) +99.7°, purity 99.91%, enantiomer content 0.058%.

[0061] HPLC chromatographic conditions for the optical isomers of 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole (the compound of formula IX and the compound of formula XIV)

[0062] Purity HPLC test method:

[0063] Fill a column with octylsilane-bonded silica gel (C8, 4.6 X 150 mm, 5 μ), and set the flow rate at 1.0 mL / min, the detection wavelength at 260 nm, and the column temperature at 25°C. Take about 10 mg of the product, dissolve and dilute to the calibration mark in a 25 mL volumetric flask with 50% methanol aqueous solution, shake well, and obtain a test solution. Accurately take 20 μL of the test solution, inject it into the liquid chromatograph, and record the chromatogram for 45 min. The theoretical plate number should not be less than 2000, calculated based on the peak of (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole.

[0064] Mobile phase: A phase (accurately weigh 2.44 g of sodium heptanesulfonate and 0.45 g of sodium acetate, dissolve in 1000 mL of water, adjust the pH to 6.0 with glacial acetic acid, and filter through a filter membrane with a pore size of 0.45 μm); B phase (mix 800 mL of acetonitrile with 200 mL of water to obtain the B phase). Set the time ratio of A and B as follows to form a gradient.

[0065] Time Phase A Phase B 0.01 85 15 15 85 15 35 60 40 40 85 15 45 85 15

[0066] Enantiomer HPLC test method:

[0067] Take the test sample, add the mobile phase to make about 0.3 mg per 1 ml solution, as the test solution. Another 2, 6-diamino-4, 5, 6, 7-tetrahydrobenzothiazole racemate control sample, add the mobile phase to make about 50 μg per 1 ml solution, as the system suitability solution. With CHIRALPAK AD-H chiral column (25 x 0.46 cm) as the chromatographic column (positive column), with n-hexane-absolute ethanol-diethylamine (85:15:0.1~0.2) as the mobile phase, the detection wavelength is 264 nm. Take the system suitability test solution 20 μl into the chromatograph, the peak order is (R)-2, 6-diamino-4, 5, 6, 7-tetrahydrobenzothiazole and (S)-2, 6-diamino-4, 5, 6, 7-tetrahydrobenzothiazole, respectively. Accurately take 20 μl of the test solution, inject into the liquid chromatograph, and record the chromatogram.

Claims

1. A chiral synthesis method of (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole, characterized in that The following steps are involved: (1) reacting 2-acetylamino-6-oxo-4,5,6,7-tetrahydrobenzothiazole compound IV with (R)-1-phenylethylamine compound V, followed by reduction with sodium borohydride to generate (S)-2-acetylamino-6-(((R)-1-phenylethyl)amino)-4,5,6,7-tetrahydrobenzothiazole compound VII; ； (2) The (S)-2-acetylamino-6-(((R)-1-phenylethyl)amino)-4,5,6,7-tetrahydrobenzothiazole compound VII obtained in the previous step is debenzylated with palladium on carbon and then hydrolyzed to obtain the (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole compound IX; 。 2. The chiral synthesis method of (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole according to claim 1, characterized in that In the step (1), the solvent used in the reaction with the R-1-phenylethylamine compound V is toluene, and the solvent used in the reduction reaction is methanol.

3. The chiral synthesis method of (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole according to claim 1, characterized in that The solvent used in the palladium-carbon reduction debenzylation step in step (2) is ethanol.

4. The chiral synthesis method of (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole according to claim 1, characterized in that The synthesis method of the 2-acetylamino-6-oxo-4,5,6,7-tetrahydrobenzothiazole compound IV comprises: S1: reacting 1,4-cyclohexanedione compound I with bromine, and then reacting with thiourea to obtain 2-amino-6-oxo-4,5,6,7-tetrahydrobenzothiazole compound III; ； S2: reacting 2-amino-6-oxo-4,5,6,7-tetrahydrobenzothiazole compound III with acetic anhydride to obtain 2-acetylamino-6-oxo-4,5,6,7-tetrahydrobenzothiazole compound IV; 。 5. The chiral synthesis method of (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole according to claim 4, characterized in that The solvent used in the reaction with bromine in step S1 is selected from methanol, and solvent water needs to be added in the reaction with thiourea; the solvent used in step S2 is water.

6. A chiral synthesis method of (R)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole, characterized in that The following steps are involved: (1) reacting 2-acetylamino-6-oxo-4,5,6,7-tetrahydrobenzothiazole compound IV with (S)-1-phenylethylamine compound X, followed by reduction with sodium borohydride to generate (R)-2-acetylamino-6-(((S)-1-phenylethyl)amino)-4,5,6,7-tetrahydrobenzothiazole compound XII; ； (2) The (R)-2-acetylamino-6-(((S)-1-phenylethyl)amino)-4,5,6,7-tetrahydrobenzothiazole compound XII obtained in the previous step is debenzylated with palladium on carbon and then hydrolyzed to obtain the (R)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole compound XIV; 。 7. The chiral synthesis method of (R)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole according to claim 6, characterized in that In the step (1), the solvent used in the reaction with the (S)-1-phenylethylamine compound V is toluene, and the solvent used in the reduction reaction is methanol.

8. The chiral synthesis method of (R)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole according to claim 6, characterized in that The solvent used in the palladium-carbon reduction debenzylation step in step (2) is ethanol.

9. The chiral synthesis method of (R)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole according to claim 6, characterized in that The synthesis method of the 2-acetylamino-6-oxo-4,5,6,7-tetrahydrobenzothiazole compound IV comprises: S1: reacting 1,4-cyclohexanedione compound I with bromine, and then reacting with thiourea to obtain 2-amino-6-oxo-4,5,6,7-tetrahydrobenzothiazole compound III; ； S2: reacting the 2-amino-6-oxo-4,5,6,7-tetrahydrobenzothiazole compound III obtained in the previous step with acetic anhydride to obtain the 2-acetylamino-6-oxo-4,5,6,7-tetrahydrobenzothiazole compound IV; 。 10. The chiral synthesis method of (R)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole according to claim 9, characterized in that The solvent used in step S1 is selected from methanol, and solvent water needs to be added during the reaction with thiourea; the solvent used in step S2 is water.

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