Preparation method of 4, 5, 6, 7-tetrahydrothiophene [3, 2-c] pyridine hydrochloride

Abstract

The invention provides a preparation method of 4, 5, 6, 7-tetrahydrothiophene [3, 2-c] pyridine hydrochloride, and relates to the technical field of organic synthesis. The preparation method comprises the following steps: mixing 2-propenyl-3-formyl thiophene, butyl carbamate and a solvent, adding acetic acid, stirring, adding sodium triethoxy borohydride, and reacting to obtain a compound III; mixing the compound III with a solvent, adding N-methylmorpholine-N-oxide, cooling, adding a tertiary butanol solution of osmium tetroxide, reacting, and purifying to obtain a compound IV; mixing the compound IV with a solvent, cooling to-78 DEG C to-65 DEG C, adding boron trifluoride diethyl etherate, reacting and purifying to obtain a compound V; mixing the compound V with a mixed solvent, adding a molecular sieve, performing ultrasonic treatment, filtering, adding an acid solvent, reacting and filtering; and the obtained product has high purity and few impurities. # imgabs0 #

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for preparing 4,5,6,7-tetrahydrothiophene[3,2-c]pyridine hydrochloride. Background Art

[0002] 4,5,6,7-Tetrahydrothieno[3,2-c]pyridine hydrochloride is a pharmaceutical intermediate, mainly used in the synthesis of platelet aggregation inhibitors such as ticlopidine, clopidogrel, prasugrel and other drugs. Its structural formula is as follows:

[0003]

[0004] Currently, there are a variety of synthetic methods for 4,5,6,7-tetrahydrothiophene[3,2-c]pyridine hydrochloride.

[0005] Route 1: 2-thiopheneacetaldehyde and aminoacetal are condensed, and in the presence of a dehydrating agent such as phosphorus oxychloride or polyphosphoric acid, a Bischler-Napieralski cyclization reaction is carried out to prepare 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (Toshio Suguro, Castaigne A et al.). However, the total yield of this process route is low, only about 10%, and the raw materials used in this method are not easy to obtain, so it is difficult to achieve industrial production.

[0006] Route 2: 2-thiopheneethylamine and formaldehyde are used as raw materials to obtain N-(2-thiopheneethyl)methyleneamine through polymerization reaction, and then cyclization is carried out under the action of acid to obtain 4,5,6,7-tetrahydrothieno[3,2-c]pyridine, but the reaction yield is low, and the total synthesis yield is about 70%.

[0007] The prior art also uses 2-thiopheneethylamine, paraformaldehyde, and hydrochloric acid ethanol solution as raw materials to synthesize 4,5,6,7-tetrahydrothiophene [3,2-c] pyridine hydrochloride in one step (Zhejiang Chemical Industry, 2010, 41 (5): 6-7), but the disadvantage is that the yield is still low (75%). There is also a method that uses 2-thiopheneethylamine, formaldehyde, and hydrochloric acid as raw materials to synthesize 4,5,6,7-tetrahydrothiophene [3,2-c] pyridine hydrochloride in one step (China New Drug Journal, 2010, 19 (15): 1314-1316), but the reaction time is long and the yield is 88.4%. There is also a method of synthesizing 4,5,6,7-tetrahydrothiophene[3,2-c]pyridine hydrochloride in one step using 2-thiopheneethylamine, formaldehyde and hydrochloric acid as raw materials (Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 2008, 47B(1):97-105), with a yield of 65%, which is also not suitable for industrial production. It can be seen that the disadvantages of the above preparation method are: 1) low yield; 2) the raw material 2-thiopheneethylamine is difficult to prepare and has a high price, resulting in a high cost of the product 4,5,6,7-tetrahydrothiophene[3,2-c]pyridine hydrochloride, etc.

[0008] Chinese patent CN 107056801 A discloses a method for synthesizing 4,5,6,7-tetrahydrothiophene[3,2-c]pyridine hydrochloride, which uses 2-thiopheneethanol and p-toluenesulfonyl chloride as raw materials to synthesize p-toluenesulfonic acid-2-thiopheneethyl ester, further reacts with formamide to synthesize N-2-thiopheneethylformamide, which is cyclized under the action of trifluoroacetic acid to form 6,7-dihydrothiophene[3,2-c]pyridine, and finally reduced with sodium borohydride and salted to obtain 4,5,6,7-tetrahydrothiophene[3,2-c]pyridine hydrochloride. Its preparation route is shown below. Although the yield is 96.52%, its purity cannot be guaranteed. As a drug intermediate, it needs to be quality controlled.

[0009]

[0010] Therefore, developing a preparation method with high yield, high purity and few impurities is an urgent problem to be solved in this field. Summary of the invention

[0011] The present invention aims to solve the above problems and provides a technical solution to achieve the above objectives. The technical solution adopted by the present invention is as follows:

[0012] In one aspect, the present invention provides a method for preparing 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride, and the reaction scheme is as follows:

[0013]

[0014] The specific steps include:

[0015] S1: 2-propenyl-3-formylthiophene, butyl carbamate and solvent are mixed, acetic acid is added, stirred for 30-40 minutes, sodium triethoxyborohydride is added, reacted for 6-10 hours, washed with water, dried and concentrated to obtain compound III;

[0016] S2: Compound III is mixed with a solvent, N-methylmorpholine-N-oxide is added, the temperature is lowered to -10°C-0°C, tert-butanol solution of osmium tetroxide is added, the reaction is carried out for 0.5-1.5h, the mixture is washed with water, dried, concentrated, and purified by column chromatography to obtain compound IV;

[0017] S3: Compound IV is mixed with a solvent, cooled to -78°C to -65°C, and boron trifluoride ether is added to react for 10-15 min, quenched, washed with water, dried, concentrated, and purified by column chromatography to obtain compound V;

[0018] S4: Compound V is mixed with a mixed solvent, molecular sieves are added, ultrasonication is performed, filtration is performed, an acid solvent is added, the temperature is raised to 45-55°C, the temperature is kept for 2-4 hours, and activated carbon is filtered; the mixed solvent is a mixed solution of methanol, acetonitrile and phosphoric acid; the acid solvent is a mixed solution of hydrochloric acid, acetic acid and tetrahydrofuran.

[0019] Preferably, in S1, the molar ratio of 2-propenyl-3-formylthiophene to butyl carbamate is 1:1-1.6; further preferably, in S1, the molar ratio of 2-propenyl-3-formylthiophene to butyl carbamate is 1:1.2-1.6; more preferably, in S1, the molar ratio of 2-propenyl-3-formylthiophene to butyl carbamate is 1:1.6;

[0020] Preferably, in S1, the molar ratio of 2-propenyl-3-formylthiophene, acetic acid and sodium triethoxyborohydride is 1:0.3-0.4:3.5-4.5; further preferably, in S1, the molar ratio of 2-propenyl-3-formylthiophene, acetic acid and sodium triethoxyborohydride is 1:0.3-0.38:4-4.5; more preferably, in S1, the molar ratio of 2-propenyl-3-formylthiophene, acetic acid and sodium triethoxyborohydride is 1:0.36:4.2;

[0021] Preferably, in S1, the solvent is selected from at least one of dichloroethane, acetonitrile and N,N-dimethylformamide; in S1, further preferably, the solvent is dichloroethane.

[0022] Preferably, in S1, the reaction temperature is 10-20°C; further preferably, in S1, the reaction temperature is 15°C.

[0023] Preferably, in S2, the solvent is a mixed solution of acetone and water, preferably, the volume ratio of acetone to water is 1-1.5:1; further preferably, the volume ratio of acetone to water is 1.2:1.

[0024] Preferably, in S2, the molar ratio of the compound III, N-methylmorpholine-N-oxide and osmium tetroxide is 1:1.5-2.5:0.01-0.05; further preferably, in S2, the molar ratio of the compound III, N-methylmorpholine-N-oxide and osmium tetroxide is 1:1.8:0.03;

[0025] Preferably, in S2, the mobile phase for column chromatography purification is hexane:ethyl acetate=8-12:1.

[0026] Preferably, in S2, the mass fraction of osmium tetroxide in the tert-butanol solution of osmium tetroxide is 3%-5%; further preferably, in S2, the mass fraction of osmium tetroxide in the tert-butanol solution of osmium tetroxide is 5%.

[0027] Preferably, in S3, the solvent is anhydrous dioxane;

[0028] Preferably, in S3, the molar ratio of boron trifluoride etherate to compound IV is 2-2.5:1; further preferably, in S3, the molar ratio of boron trifluoride etherate to compound IV is 2.4:1.

[0029] Preferably, in S3, the mobile phase for column chromatography purification is dichloromethane:acetonitrile:triethylamine=20-24:1-2:0.5-1; further preferably, in S3, the mobile phase for column chromatography purification is dichloromethane:acetonitrile:triethylamine=22:2:1;

[0030] Preferably, in S4, the volume ratio of methanol, acetonitrile and phosphoric acid in the mixed solvent is 1:1-1.2:0.05-0.1; further preferably, in S4, the volume ratio of methanol, acetonitrile and phosphoric acid in the mixed solvent is 1:1.1:0.08.

[0031] Preferably, in S4, the mass fraction of the phosphoric acid solution is 10%-12%; further preferably, in S4, the mass fraction of the phosphoric acid solution is 12%.

[0032] Preferably, in S4, the volume ratio of hydrochloric acid, acetic acid and tetrahydrofuran is 80-85:1-5:1:5; further preferably, in S4, the volume ratio of hydrochloric acid, acetic acid and tetrahydrofuran is 82:4:4.

[0033] Compared with the prior art, the present invention has the following beneficial effects:

[0034] The preparation method of the present invention optimizes raw materials, ratios and reaction conditions, so that the final product obtained has not only high yield but also high purity; and by optimizing the process of preparing hydrochloride, the purity of the product is significantly improved and the impurity content is reduced. DETAILED DESCRIPTION

[0035] In order to make the technical means, creative features, purpose and effect of the present invention easy to understand, the present invention is further explained below in conjunction with specific embodiments, but the following embodiments are only preferred embodiments of the present invention, not all. Based on the embodiments in the implementation mode, other embodiments obtained by those skilled in the art without making creative work all belong to the protection scope of the present invention. It is worth noting that the raw materials used in the present invention are all common commercial products, and their sources are not specifically limited. The technology and scientific terms used in the embodiments have the meanings commonly understood by those of ordinary skill in the art to which the present invention belongs.

[0036] Glossary:

[0037] DCM: dichloromethane;

[0038] MeCN: acetonitrile;

[0039] DMF: N,N-dimethylformamide;

[0040] NaIO4: sodium periodate;

[0041] NMO: N-methylmorpholine-N-oxide;

[0042] OsO4: osmium tetroxide;

[0043] THF: tetrahydrofuran;

[0044] BF3·Et2O: Boron trifluoride etherate;

[0045] Example 1

[0046] A method for preparing 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride, the reaction route is as follows:

[0047]

[0048] The specific steps include:

[0049] S1: 2-Propylene-3-formylthiophene (0.1 mol, 15.4 g), butyl carbamate (0.16 mol, 18.7 g) were mixed with 1000 mL of dichloromethane, acetic acid (0.036 mol, 2.16 g, 5.34 mL) was added, and the mixture was stirred for 30 min. Sodium triethoxyborohydride (0.42 mol, 50.8 g) was added, and the mixture was reacted at 15°C for 6.5 h. 100 mL of sodium bicarbonate solution was added, and the mixture was washed with water, extracted with DCM (500 mL x 3), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain compound III, tert-butyl ((2-alkenylthiophene-3-acyl)methyl)carbamate 24.04 g, 95%;

[0050] 1 H NMR(600MHz, CDCl3)7.09(d,J=5.14Hz,1H),6.93(d,J=5.13Hz,1H),5.94(ddt,J=17.31,9.65,6.33,6.33H z,1H),5.05-5.12(m,2H),4.66(br.s.,1H),4.22(d,J=4.95Hz,2H),3.54(d,J=6.42Hz,2H),1.45(s,10H);

[0051] 13 C NMR (150MHz, CDCl3)156.0,138.7,136.6,135.1,128.9,123.1,116.6,79.8,38.1,32.2,28.7;

[0052] S2: Compound III (0.095 mol, 24.02 g) was mixed with 1000 mL of a mixed solution of acetone and deionized water (volume ratio of acetone to water was 1.2:1), N-methylmorpholine-N-oxide (0.171 mol, 23.1 g) was added, the temperature was lowered to -10°C-0°C, 5 wt% osmium tetroxide solution in tert-butanol (18.13 mL, 0.0029 mol, 2 mol%) was added, and the reaction was continued for 0. .5h, add Na2S2O3 (47mg, 0.3mmol) to quench, wash with water, extract with chloroform (500mLx3), add anhydrous sodium sulfate to dry, filter, dry, concentrate, and purify by column chromatography (hexane: ethyl acetate = 8:1) to obtain compound IV, 6-hydroxy-6,7-dihydrothiophene [3,2-c] tert-butylpyridine-5 (4H) -carboxylate 22.3g, 92%, HPLC purity 99.8%;

[0053] 1H NMR(600MHz, CDCl3)7.15(1H,d,J=5.14Hz),6.81(1H,d,J=5.14Hz),6.15(1H,br.s.),4. 70(1H,d,J=15.96Hz),4.29(1H,dt,J=16.09,1.86Hz),3.03-3.16(2H,m),1.51(10H,s);

[0054] 13 C NMR (150MHz, CDCl3)155.2,131.4,129.9,125.2,124.0,81.2,74.2,41.2,32.1,28.8;

[0055] S3: Compound IV (0.087 mol, 22.3 g) was mixed with 1000 mL of anhydrous dioxane, cooled to -78°C to -65°C, and boron trifluoride etherate (0.209 mol, 29.67 g) was added. The mixture was reacted for 10-15 min, quenched with 50 mL of 2 M sodium hydroxide solution, washed with water, extracted with DCM (500 mL x 3), dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (dichloromethane: acetonitrile: triethylamine = 22:2:1) to obtain compound V, 4,5,6,7-tetrahydrothiophene [3,2-c] pyridine 11.87 g, 98%, HPLC purity 99.9%;

[0056] 1 H NMR (300MHz, CDCl3)7.05(d,1H),6.74(d,1H),3.93(m,2H),3.15(t,2H),2.81(t,2H).

[0057] S4: 11.87 g of compound V was mixed with 500 mL of a mixed solution of methanol, acetonitrile and 12 wt% phosphoric acid (the volume ratio of methanol, acetonitrile and phosphoric acid was 1:1.1:0.08), molecular sieves were added, ultrasonicated for 30 min, filtered, 100 mL of a mixed solution of 25 wt% hydrochloric acid, 30 wt% acetic acid and tetrahydrofuran (the volume ratio of hydrochloric acid, acetic acid and tetrahydrofuran was 82:4:4) was added, the temperature was raised to 45°C, kept warm for 2 h, filtered with activated carbon, and 15.13 g of 4,5,6,7-tetrahydrothiophene[3,2-c]pyridine hydrochloride was obtained, 99%, and the HPLC purity was 99.9%.

[0058] Example 2

[0059] A method for preparing 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride, the reaction route is as follows:

[0060]

[0061] The specific steps include:

[0062] S1: 2-Propylene-3-formylthiophene (0.1 mol, 15.4 g), butyl carbamate (0.1 mol, 11.7 g) were mixed with 1000 mL of dichloromethane, acetic acid (0.036 mol, 2.16 g, 5.34 mL) was added, and the mixture was stirred for 30 min. Sodium triethoxyborohydride (0.35 mol, 42.34 g) was added, and the mixture was reacted at 10°C for 6.5 h. 100 mL of sodium bicarbonate solution was added, and the mixture was washed with water, extracted with DCM (500 mL x 3), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain compound III, tert-butyl ((2-alkenylthiophene-3-acyl)methyl)carbamate 23.79 g, 94%;

[0063] S2: Compound III (0.094 mol, 23.79 g) was mixed with 1000 mL of a mixed solution of acetone and deionized water (volume ratio of acetone to water was 1.5:1), N-methylmorpholine-N-oxide (0.141 mol, 19.05 g) was added, the temperature was lowered to -10°C-0°C, 5 wt% tert-butyl alcohol solution of osmium tetroxide (5.88 mL, 0.94 mmol, 2 mol%) was added, and the reaction was continued for 0. 5h, add Na2S2O3 (47mg, 0.3mmol) to quench, wash with water, extract with chloroform (500mLx3), add anhydrous sodium sulfate to dry, filter, dry, concentrate, and purify by column chromatography (hexane: ethyl acetate = 8: 1) to obtain compound IV, 6-hydroxy-6,7-dihydrothiophene [3,2-c] tert-butylpyridine-5 (4H) -carboxylate 22.07g, 91%, HPLC purity 99.7%;

[0064] S3: Compound IV (0.086 mol, 22.07 g) was mixed with 1000 mL of anhydrous dioxane, cooled to -78°C to -65°C, and boron trifluoride etherate (0.172 mol, 24.41 g) was added. The mixture was reacted for 10-15 min, quenched with 50 mL of 2 M sodium hydroxide solution, washed with water, extracted with DCM (500 mL x 3), dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (dichloromethane: acetonitrile: triethylamine = 22:2:1) to obtain compound V, 4,5,6,7-tetrahydrothiophene [3,2-c] pyridine 11.67 g, 97.5%, HPLC purity 99.9%;

[0065] S4: 11.67 g of compound V was mixed with 500 mL of a mixed solution of methanol, acetonitrile and 12 wt% phosphoric acid (the volume ratio of methanol, acetonitrile and phosphoric acid was 1:1.1:0.08), molecular sieves were added, ultrasonicated for 30 min, filtered, 100 mL of a mixed solution of 25 wt% hydrochloric acid, 30 wt% acetic acid and tetrahydrofuran (the volume ratio of hydrochloric acid, acetic acid and tetrahydrofuran was 80:1:2) was added, the temperature was raised to 45°C, kept warm for 2 h, and filtered with activated carbon to obtain 14.43 g of 4,5,6,7-tetrahydrothiophene[3,2-c]pyridine hydrochloride, 98%, HPLC purity was 99.9%.

[0066] Comparative Example 1

[0067] A method for preparing 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride, the reaction route is as follows:

[0068]

[0069] The specific steps include:

[0070] S1: 2-Propylene-3-formylthiophene (0.1 mol, 15.4 g), butyl carbamate (0.2 mol, 23.4 g) were mixed with 1000 mL of dichloromethane, acetic acid (0.02 mol, 1.2 g, 2.97 mL) was added, and the mixture was stirred for 30 min. Sodium triethoxyborohydride (0.5 mol, 60.49 g) was added, and the mixture was reacted at 15°C for 6.5 h. 100 mL of sodium bicarbonate solution was added, and the mixture was washed with water, extracted with DCM (500 mL x 3), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain compound III, tert-butyl ((2-alkenylthiophene-3-yl)methyl)carbamate 20.52 g, 81%;

[0071] S2: Compound III (0.081 mol, 20.52 g) was mixed with 1000 mL of a mixed solution of THF and deionized water (the volume ratio of THF to water was 1.2:1), N-methylmorpholine-N-oxide (0.081 mol, 10.95 g) was added, the temperature was lowered to -10°C-0°C, 5 wt% tert-butyl alcohol solution of osmium tetroxide (36.26 mL, 0.0058 mol, 2 mol%) was added, and the reaction was continued. 0.5h, add Na2S2O3 (47mg, 0.3mmol) to quench, wash with water, extract with chloroform (500mLx3), add anhydrous sodium sulfate to dry, filter, dry, concentrate, and purify by column chromatography (hexane: ethyl acetate = 10: 1) to obtain compound IV, 6-hydroxy-6,7-dihydrothiophene [3,2-c] tert-butylpyridine-5 (4H) -carboxylate 15.51g, 75%, HPLC purity 89.5%;

[0072] S3: Compound IV (0.061 mol, 15.51 g) was mixed with 1000 mL of anhydrous dioxane, cooled to -78°C to -65°C, and added with boron trifluoride etherate (0.061 mol, 8.66 g). The mixture was reacted for 10-15 min, and quenched with 50 mL of 2 M sodium hydroxide solution. The mixture was washed with water, extracted with DCM (500 mL x 3), dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (dichloromethane: acetonitrile = 22:2) to obtain compound V, 4,5,6,7-tetrahydrothiophene [3,2-c] pyridine 6.03 g, 71%, with a HPLC purity of 82%;

[0073] S4: Compound V (6.03 g) was mixed with methanol (500 mL), ultrasonicated for 30 min, filtered, 27 wt% ethanol-hydrogen chloride solution (100 mL) was added, the temperature was raised to 45°C, kept warm for 2 h, and filtered with activated carbon to obtain 4,5,6,7-tetrahydrothiophene[3,2-c]pyridine hydrochloride (6.47 g, 85%) with a HPLC purity of 79%.

[0074] Comparative Example 2

[0075] A method for preparing 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride, the reaction route is as follows:

[0076]

[0077] The specific steps include:

[0078] S1: 2-Propylene-3-formylthiophene (0.1 mol, 15.4 g), butyl carbamate (0.16 mol, 18.7 g) were mixed with 1000 mL of dichloromethane, trifluoroacetic acid (0.036 mol, 4.10 g) was added, and the mixture was stirred for 30 min. Triethylsilane (0.42 mol, 48.84 g) was added, and the mixture was reacted at 15°C for 6.5 h. 100 mL of sodium bicarbonate solution was added, and the mixture was washed with water, extracted with DCM (500 mL x 3), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain compound III, tert-butyl ((2-alkenylthiophene-3-acyl)methyl)carbamate 21.28 g, 82%;

[0079] S2: Compound III (0.082 mol, 21.28 g) was mixed with 1000 mL of a mixed solution of acetone and deionized water (the volume ratio of acetone to water was 1.2:1), sodium periodate (0.148 mol, 31.66 g) was added, the temperature was lowered to -10°C-0°C, 5 wt% tert-butanol solution of osmium tetroxide (18.13 mL, 0.0029 mol, 2 mol%) was added, and the reaction was carried out for 0.5 h. Add Na2S2O3 (47 mg, 0.3 mmol) to quench, wash with water, extract with chloroform (500 mL x 3), add anhydrous sodium sulfate to dry, filter, dry, concentrate, and purify by column chromatography (hexane: ethyl acetate = 8: 1) to obtain compound IV, 6-hydroxy-6,7-dihydrothiophene [3,2-c] tert-butylpyridine-5 (4H) -carboxylate 16.75 g, 80%, HPLC purity 95.6%;

[0080] S3: Compound IV (0.066 mol, 16.75 g) was mixed with DCM 1000 mL, cooled to -78°C to -65°C, triethylsilane (0.158 mol, 21.28 g) and BF3·Et2O (0.158 mol, 22.42 g) were added, reacted for 10-15 min, quenched by adding 50 mL 2M sodium hydroxide solution, washed with water, extracted with DCM (500 mL x 3), dried by adding anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (dichloromethane: acetonitrile: triethylamine = 22:2:1) to obtain compound V, 4,5,6,7-tetrahydrothiophene [3,2-c] pyridine 7.81 g, 85%, HPLC purity 92.5%;

[0081] S4: 7.81 g of compound V was mixed with 500 mL of a mixed solution of methanol and 12 wt% phosphoric acid (the volume ratio of methanol, acetonitrile and phosphoric acid was 1:0.08), molecular sieves were added, ultrasonicated for 30 min, filtered, 100 mL of a mixed solution of 25 wt% hydrochloric acid, 30 wt% acetic acid and tetrahydrofuran (the volume ratio of hydrochloric acid, acetic acid and tetrahydrofuran was 82:4:4) was added, the temperature was raised to 45°C, kept warm for 2 h, and filtered with activated carbon to obtain 8.87 g of 4,5,6,7-tetrahydrothiophene[3,2-c]pyridine hydrochloride, 90%, HPLC purity was 81%.

[0082] Comparative Example 3

[0083] Compared with Example 1, only S4 is changed to:

[0084] S4: 11.87 g of compound Ⅴ was mixed with 500 mL of methanol and acetonitrile (the volume ratio of methanol to acetonitrile was 1:1.1), molecular sieves were added, ultrasonicated for 30 min, filtered, 100 mL of a mixed solution of 25 wt% hydrochloric acid, 30 wt% acetic acid and tetrahydrofuran (the volume ratio of hydrochloric acid, acetic acid and tetrahydrofuran was 82:4:4) was added, the temperature was raised to 45°C, kept warm for 2 h, and filtered with activated carbon to obtain 14.06 g of 4,5,6,7-tetrahydrothiophene[3,2-c]pyridine hydrochloride, 92%, with an HPLC purity of 82%.

[0085] Comparative Example 4

[0086] Compared with Example 1, only S4 is changed to:

[0087] S4: 11.87 g of compound V was mixed with 500 mL of a mixed solution of methanol, acetonitrile and 12 wt% phosphoric acid (the volume ratio of methanol, acetonitrile and phosphoric acid was 1:1.1:0.08), molecular sieves were added, ultrasonicated for 30 min, filtered, 100 mL of a mixed solution of 25 wt% hydrochloric acid and tetrahydrofuran (the volume ratio of hydrochloric acid to tetrahydrofuran was 82:4) was added, the temperature was raised to 45°C, kept warm for 2 h, and filtered with activated carbon to obtain 13.60 g of 4,5,6,7-tetrahydrothiophene[3,2-c]pyridine hydrochloride, 89%, with an HPLC purity of 79%.

[0088] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A method for preparing 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride, the reaction route is as follows: The specific steps include: S1: 2-propenyl-3-formylthiophene, butyl carbamate and solvent are mixed, acetic acid is added, stirred for 30-40 minutes, sodium triethoxyborohydride is added, reacted for 6-10 hours, washed with water, dried and concentrated to obtain compound III; S2: Compound III is mixed with a solvent, N-methylmorpholine-N-oxide is added, the temperature is lowered to -10°C-0°C, tert-butanol solution of osmium tetroxide is added, the reaction is carried out for 0.5-1.5h, the mixture is washed with water, dried, concentrated, and purified by column chromatography to obtain compound IV; S3: Compound IV is mixed with a solvent, cooled to -78°C to -65°C, and boron trifluoride ether is added to react for 10-15 min, quenched, washed with water, dried, concentrated, and purified by column chromatography to obtain compound V; S4: Compound V is mixed with a mixed solvent, molecular sieves are added, ultrasonication is performed, filtration is performed, an acid solvent is added, the temperature is raised to 45-55°C, the temperature is kept for 2-4 hours, and activated carbon is filtered; the mixed solvent is a mixed solution of methanol, acetonitrile and phosphoric acid; the acid solvent is a mixed solution of hydrochloric acid, acetic acid and tetrahydrofuran.

2. The preparation method according to claim 1, characterized in that: In S1, the molar ratio of the 2-propenyl-3-formylthiophene to butyl carbamate is 1:1-1.6; the molar ratio of the 2-propenyl-3-formylthiophene, acetic acid and sodium triethoxyborohydride is 1:0.3-0.4:3.5-4.

5.

3. The preparation method according to claim 1, characterized in that: In S1, the reaction temperature is 10-20°C.

4. The preparation method according to claim 1, characterized in that: In S2, the solvent is a mixed solution of acetone and water; the volume ratio of acetone to water is 1-1.5:1; the molar ratio of compound III, N-methylmorpholine-N-oxide and osmium tetroxide is 1:1.5-2.5:0.01-0.

05.

5. The preparation method according to claim 1, characterized in that: In S2, the mobile phase of the column chromatography purification is hexane:ethyl acetate=8-12:

1.

6. The preparation method according to claim 1, characterized in that: In S3, the molar ratio of boron trifluoride etherate to compound IV is 2-2.5:

1.

7. The preparation method according to claim 1, characterized in that: In S3, the mobile phase of the column chromatography purification is dichloromethane:acetonitrile:triethylamine=20-24:1-2:0.5-1.

8. The preparation method according to claim 1, characterized in that: In S4, in the mixed solvent, the volume ratio of methanol, acetonitrile and phosphoric acid is 1:1-1.2:0.05-0.

1.

9. The preparation method according to claim 1, characterized in that: In S4, the mass fraction of the phosphoric acid solution is 10%-12%.

10. The preparation method according to claim 1, characterized in that: In S4, the volume ratio of hydrochloric acid, acetic acid and tetrahydrofuran is 80-85:1-5:1:5.

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