A kind of preparation method of high-purity lafutidine

Abstract

The present invention relates to the preparation of high-purity lafutidine. Malein-1,4-diol is used as a starting material, reacted with dichlorothionyl to generate cyclic sulfinic acid lactone; then reacted with bis-Boc-imide potassium salt to generate bis-Boc-malein-1-amine-4-alcohol; then reacted with 4-(piperidin-1-yl)methyl-2-halopyridine to generate LAF-SMA through etherification reaction; compound LAF-SMA is then deprotected from bis-Boc to obtain LAF-01, and then subjected to amine ester exchange reaction with active ester LAF-SM2 to obtain lafutidine. The preparation method avoids the generation of dihydrolafutidine impurities, thereby obtaining high-purity lafutidine.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and in particular to lafutidine. The structure of lafutidine is as follows:

[0002] Background Art

[0003] Lafutidine is a highly effective and long-acting second-generation histamine H2 receptor antagonist. It was jointly developed by Fuji and Taiho Pharmaceuticals of Japan and was launched in Japan on April 19, 2000 after approval by the Ministry of Health, Labor and Welfare of Japan. At present, more than ten domestic pharmaceutical companies have obtained production approvals for raw materials or preparations.

[0004] Lafutidine's ability to block histamine H2 receptors is much stronger than other traditional histamine H2 receptor antagonists. It has a strong and lasting effect in inhibiting gastric acid, and can continuously inhibit the basal and nocturnal secretion of gastric acid and pepsin, as well as inhibit gastric acid secretion caused by stimulating factors such as tetragastrin, choline, and gastric dilatation. Lafutidine can protect the gastric mucosa by enhancing the barrier function of the gastric mucosa, effectively resisting damaging factors, and promoting the healing of gastric ulcers.

[0005] Studies have shown that lafutidine is significantly better than famotidine in improving the healing of gastric ulcers. It can make the patient's ulcer surface heal faster, shorten the bleeding time, and reduce the length of hospital stay.

[0006] Lafutidine is an oral drug, and its main dosage forms are tablets, dispersible tablets, capsules, and granules. Its dosage is: 10 mg / time, 2 times / day; take after meals or before bedtime.

[0007] At present, the main method for preparing lafutidine is: etherification reaction of compound LAF-SM1-01-C1 with compound LAF-SM1-02-S1 (tetrahydropyran mono-protected maleic acid) to obtain LAF-SM1-02, and deprotection to obtain compound LAF-SM1-03; or direct etherification of compound LAF-SM1-01-Cl with compound LAF-SM1-02-S0 (maleic acid) to obtain compound LAF-SM1-03; then converting LAF-SM1-03 into the corresponding chloro compound (compound LAF-SM1-04-Cl) or methyl sulfonate (LAF-SM1-04-Ms); the product obtained by N-alkylation reaction of compound LAF-SM1-04-Cl or LAF-SM1-04-Ms with potassium salt of phthalimide is used to form a salt with maleic acid to obtain LAF-SM1. The synthetic route is shown in the following formula:

[0008]

[0009] When preparing compound LAF-SM1-03, if compound LAF-SM1-01-Cl is etherified with compound LAF-SM1-02-S1 to first obtain compound LAF-SM1-02, and then deprotection is performed to obtain LAF-SM1-03, the preparation method of the desired compound LAF-SM1-02-S1 is to react LAF-SM1-02-S0 with dihydropyran, but the reaction target is single protection, and the selectivity of single protection is relatively poor, a large amount of double protection impurity LAF-SM1-02-imp will be generated, and it is also difficult to separate the single protection product from the double protection impurity, and it is difficult to obtain high-quality LAF-SM1-02-S1 by simple treatment; and the price of dihydropyran is also relatively high; it is not a good choice for industrial production.

[0010] Among them, LAF-SM1-02-S1 and its impurity LAF-SM1-02-imp are obtained by the following reaction:

[0011]

[0012] If LAF-SM1-03 is obtained by direct etherification of compound LAF-SM1-01-Cl and compound LAF-SM1-02-S0, a large excess of LAF-SM1-02-S0 (LAF-SM1-02-S0 is about 15 to 20 times the molar amount of LAF-SM1-01-Cl) needs to be added to suppress the formation of the dietherified impurity LAF-SM1-03-imp. Maleic anhydride is not easy to recycle and reuse due to its relatively special physical and chemical properties, such as good water solubility and high boiling point. Therefore, the preparation of LAF-SM1-03 by this method also greatly increases the production cost and the subsequent three waste disposal costs.

[0013] Among them, LAF-SM1-03 and its impurity LAF-SM1-03-imp are obtained by the following reaction:

[0014]

[0015] The method for preparing Lafutidine via compound LAF-SM1 is as follows: compound LAF-SM1 or its corresponding free base is subjected to hydrazine hydrate to remove the phthaloyl protection to obtain compound LAF-01; LAF-01 is then subjected to amine ester exchange with LAF-SM2 to obtain the target product Laftidine. The synthetic route is shown in the following formula:

[0016]

[0017] In the synthesis of Gabriel amine, hydrazine hydrate is often used to hydrazinolyze phthalimide derivatives to prepare the corresponding amines. Once there is a suitable olefin C=C double bond in the substrate structure, hydrazine hydrate and its oxidative decomposition product, the imine, are likely to reduce the olefin to the corresponding alkyl structure. The inferred mechanism is as follows:

[0018]

[0019] Therefore, when LAF-01 is prepared by the above method, it is very likely to generate alkanes with reduced double bonds; when the generated reduction product LAF-01-DH acts as an impurity, it will be transferred to the final product to generate the impurity dihydrolafutidine Lafutidine-DH. Its structure is very similar to Lafutidine, and it is difficult to remove it through refining, resulting in a significant decrease in the purity of the obtained Lafutidine, which does not meet the pharmaceutical standards. Usually, the proportion of Lafutidine-DH is between 0.2 and 1.0%.

[0020]

[0021] Based on the above reasons, it is particularly important to develop a method for preparing high-purity Lafutidine. Summary of the invention

[0022] The present invention adopts the strategy of replacing the phthaloyl-protected amino group in LAF-SM1 with a bis-Boc-protected amino group to avoid the defect of olefins being reduced to alkanes during the synthesis of Gabriel amine. In the process of removing the bis-Boc-protecting group, hydrazine hydrate is not required, so that the olefin C=C double bond in the substrate will not be reduced to an alkane by hydrazine hydrate; the chemical purity of the final product Lafutidine is improved. The structure of LAF-SMA with a bis-Boc-protected group is as follows:

[0023]

[0024] The synthetic routes for preparing LAF-SMA and Lafutidine from LAF-SMA are as follows:

[0025]

[0026] Among them, X=Cl, Br.

[0027] Compound LAF-SM1-02-S0 (cis-1,4-diol) is used as a starting material and reacted with dichlorothionyl to generate cyclic sulfenic acid lactone LAF-SMA-01; compound LAF-SMA-01 is then reacted with bis-Boc-imide potassium salt LAF-SMA-S2 to generate bis-Boc-cis-4-ol compound LAF-SMA-02; compound LAF-SMA-02 is then subjected to etherification reaction with 4-(piperidin-1-yl)methyl-2-halopyridine LAF-SM1-01-X to generate LAF-SMA; compound LAF-SMA is then deprotected from bis-Boc- to obtain LAF-01, and compound LAF-01 is then subjected to amine ester exchange reaction with active ester LAF-SM2 to obtain Lafutidine.

[0028] The present invention adopts a method for preparing compound LAF-01 via compound LAF-SMA, avoiding the disadvantage that the olefin C=C double bond will be reduced to alkane by hydrazine hydrate when preparing compound LAF-01 via LAF-SM1 in the traditional method, and obtaining high-purity Lafutidine. Among them, compound LAF-SMA-01 is easily obtained from LAF-SM1-02-S0 and dithionyl chloride, and can be reacted with bis-Boc-imide potassium salt compound LAF-SMA-02-S2 without purification to obtain LAF-SMA-02; compound LAF-SMA-02 has only one hydroxyl group as a reaction site, and when performing etherification reaction with compound LAF-SM1-01-X, the amount of compound LAF-SMA-02 does not need to be too much, so that the conversion rate of compound LAF-SM1-01-X to generate the target product can be greatly improved, and the production cost and the cost of three waste treatment are greatly reduced.

[0029] Abbreviations:

[0030] BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 : The lafutidine HPLC collection of illustrative plates prepared among the embodiment 9

[0032] Figure 2 : The lafutidine HPLC collection of illustrative plates prepared in Comparative Example 3

[0033] Figure 3 : The lafutidine HPLC collection of illustrative plates prepared in Comparative Example 4

[0034] Figure 4 : Lafutidine HPLC collection of illustrative plates (220nm and 276nm dual wavelength detection) prepared in Comparative Example 4

[0035] Figure 5: The isolated dihydrolafutidine HPLC spectrum in Comparative Example 4

[0036] Figure 6 : HPLC spectrum of lafutidine and dihydrolafutidine mixed at 1:1 (w / w)

[0037] Figure 7 :Lafutidine 1H-NMR spectrum

[0038] Figure 8 :Dihydrolafutidine 1H-NMR spectrum DETAILED DESCRIPTION

[0039] Example 1 Preparation of tert-butyl (2Z)-4-hydroxy-2-butene-1-aminodicarboxylate

[0040]

[0041] Add 800 g of dichloromethane and 93 g (1.366 mol) of imidazole to the reaction bottle, control the temperature not to exceed 20°C, and slowly drop 162 g (1.362 mol) of dichlorothionyl; after the addition is complete, keep the temperature at 10-20°C to obtain a reserve solution 1.

[0042] Add 400g of dichloromethane and 100g (1.135mol) of cis-1,4-diol to another reaction bottle, stir evenly, and cool to 5-10°C; add the prepared reserve solution 1 dropwise. After the addition is complete, keep warm at 15-25°C and continue stirring for 1-2 hours. Add 300g of water to the reaction solution, stir and wash thoroughly, separate the aqueous phase, and extract once with 400g of dichloromethane; combine the organic phases, dry with anhydrous sodium sulfate, filter, collect the filtrate, and concentrate under reduced pressure to obtain the residue LAF-SMA-01 (2-oxo-4,7-dihydro-1,3,2-dioxysulfur ) about 160g.

[0043] To the residue obtained above, add about 500 g of DMF, add 260 g (1.018 mol) of LAF-SMA-02-S2 (bis-Boc-imide potassium salt), stir and heat to 90-100°C, and react for 2-3 hours; after the reaction is completed, cool to 10-20°C, add 1200 g of water; add isopropyl ether and extract three times (800 g + 600 g + 400 g); combine the organic phases, dry with anhydrous sodium sulfate, filter, collect the filtrate, concentrate under reduced pressure, add ethyl acetate / n-heptane, cool, stir and crystallize; filter, collect the solid, and dry to obtain about 222 g (theoretical amount: 292.6 g) of LAF-SMA-02; yield: 75.9%.

[0044] 1H-NMR (CDCl3, 400MHz): 1.44 (s, 18H); 2.58~2.61 (t, 1H); 4.29~4.33 (m, 2H); 4.41~4.45 (m, 2H); 5.48~5.52 (m, 1H); 5.83~5.87 (m, 1H).

[0045] Example 2 Preparation of tert-butyl (2Z)-4-hydroxy-2-butene-1-aminodicarboxylate

[0046]

[0047] Add 1000 g of dichloromethane and 170 g (1.429 mol) of benzotriazole to the reaction bottle, control the temperature not to exceed 20°C, and slowly drop 170 g (1.427 mol) of thionyl chloride; after the addition is complete, keep the temperature at 10-20°C to obtain a reserve solution 1.

[0048] Add 400g of dichloromethane to another reaction bottle, add 100g (1.135mol) of cis-1,4-diol, stir evenly, cool to 5-10°C; add the prepared reserve solution 1 dropwise. After the addition is complete, keep warm at 15-25°C and continue stirring for 1-2 hours. Filter and collect the solid (the solid is benzotriazole hydrochloride). Add 400g of water to the obtained filtrate, stir and wash thoroughly, separate the aqueous phase, and extract once with 400g of dichloromethane; combine the organic phases, dry with anhydrous sodium sulfate, filter, collect the filtrate, and concentrate under reduced pressure to obtain the residue LAF-SMA-01 (2-oxo-4,7-dihydro-1,3,2-dioxysulfur ) about 165g.

[0049] To the residue obtained above, add about 500 g of DMAc, add 270 g (1.057 mol) of LAF-SMA-02-S2 (bis-Boc-imide potassium salt), heat to 90-100°C, and react for 2-3 hours; after the reaction is completed, cool to 10-20°C, add 1500 g of water; add isopropyl ether and extract three times (800 g + 600 g + 400 g); combine the organic phases, dry with anhydrous sodium sulfate, filter, collect the filtrate, concentrate under reduced pressure, add ethyl acetate / n-heptane, cool, stir and crystallize; filter, collect the solid, and dry to obtain about 251 g (theoretical amount: 303.8 g) of LAF-SMA-02; yield: 82.6%.

[0050] Example 3 Preparation of tert-butyl (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-butene-1-aminodicarboxylate

[0051]

[0052] Add 600g of tetrahydrofuran to the reaction bottle, cool to 0-5°C, add 15g (375.0mmol) of 60% sodium hydride, control the temperature not to exceed 10°C, and then add 90g (313.2mmol) of LAF-SMA-02 in batches; after addition, keep warm at 20-30°C and stir for about 1hr; then add 50g (237.3mmol) of LAF-SM1-01-Cl dropwise; after the addition is complete, slowly heat to 60-70°C, reflux reaction for 4-6hr; after the reaction is complete, add aqueous ammonium chloride to quench the reaction, and adjust the system pH to 12-13 with aqueous potassium carbonate solution; after adjustment, add ethyl acetate to extract three times (300g+200g+100g); combine the organic phases; dry with anhydrous sodium sulfate; filter, collect the filtrate, and concentrate under reduced pressure to obtain the product LAF-SMA about 83g (theoretical amount: 109.5g); yield: 75.8%.

[0053] Example 4 Preparation of tert-butyl (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-butene-1-aminodicarboxylate

[0054]

[0055] Add 900g toluene and 56g (499.0mmol) potassium tert-butoxide to the reaction bottle; control the temperature not to exceed 20°C, and then add 135g (469.9mmol) LAF-SMA-02 in batches; then add 100g (391.9mmol) LAF-SM1-01-Br dropwise; after the addition is complete, slowly heat to 90-110°C, and reflux for 5-8hr; after the reaction is complete, add 400g water to quench the reaction; let stand and separate the liquid; separate the organic phase, and add isopropyl acetate to the aqueous phase and extract twice (300g+200g); combine the organic phases; dry with anhydrous sodium sulfate; filter, collect the filtrate, and concentrate under reduced pressure to obtain the product LAF-SMA about 143g (theoretical amount: 180.9g); yield: 79.0%.

[0056] Example 5 Preparation of tert-butyl (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-butene-1-aminodicarboxylate

[0057]

[0058] Add 200g of dimethyl sulfoxide (DMSO) to the reaction bottle, add 20g (320.8mmol) of potassium hydroxide (90% content), 36g (260.5mmol) of anhydrous potassium carbonate, and then add 82g (285.4mmol) of LAF-SMA-02; then add 50g (237.3mmol) of LAF-SM1-01-Cl; after the addition, heat to 60-70°C and react for 3-5hr; after the reaction is completed, add 500g of water to quench the reaction; add isopropyl acetate and extract three times (500g+200g+100g); combine the organic phases; dry with anhydrous sodium sulfate; filter, collect the filtrate, and concentrate under reduced pressure to obtain the product LAF-SMA about 62g (theoretical amount: 109.5g); yield: 56.6%.

[0059] Example 6 Preparation of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-butene-1-amine

[0060]

[0061] Add 640 g of dichloromethane and 80 g (173.3 mmol) of LAF-SMA to the reaction bottle; cool to 0-10°C, add 120 g (1052.4 mmol) of trifluoroacetic acid dropwise while stirring; heat to 30-35°C, continue stirring for about 2 hours; solid precipitates in the system, filter and collect the solid; disperse the obtained solid in 300 g of isopropyl ether, add 300 g of 40% potassium carbonate aqueous solution; stir well, stand and separate, and extract the aqueous phase with 200 g of isopropyl ether; combine the organic phases; dry with anhydrous sodium sulfate; filter, collect the filtrate, and concentrate under reduced pressure to obtain about 33 g of product LAF-01 (theoretical amount: 45.30 g); yield: 72.9%.

[0062] Example 7 Preparation of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-butene-1-amine

[0063]

[0064] Add 700 g of ethyl acetate and 140 g (303.3 mmol) of LAF-SMA to the reaction bottle; cool to 0-10°C, and add 600 g (1974.8 mmol) of 12% hydrogen chloride ethyl acetate solution dropwise with stirring; after the addition is complete, heat to 30-40°C, and continue stirring for about 2 hours; solid precipitates in the system, filter, and collect the solid; disperse the obtained solid in 500 g of ethyl acetate, add 400 g of 40% potassium carbonate aqueous solution; stir well, stand and separate, and extract the aqueous phase with 400 g of ethyl acetate; combine the organic phases; dry over anhydrous sodium sulfate; filter, collect the filtrate, and concentrate under reduced pressure to obtain the product LAF-01 about 70 g (theoretical amount: 79.27 g); yield: 88.3%.

[0065] Example 8 Preparation of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-butene-1-amine

[0066]

[0067] Add 600 g of acetonitrile and 60 g (130.0 mmol) of LAF-SMA to the reaction bottle; cool to 0-10°C, add 90 g (936.5 mmol) of methanesulfonic acid dropwise while stirring; slowly heat to 30-40°C, continue stirring for about 2 hours; solid precipitates in the system, filter and collect the solid; disperse the obtained solid in 300 g of toluene, add 200 g of 40% potassium carbonate aqueous solution; stir well, let stand to separate the liquids, and extract the aqueous phase with 200 g of toluene; combine the organic phases; dry over anhydrous sodium sulfate; filter, collect the filtrate, and concentrate under reduced pressure to obtain about 27 g of product LAF-01 (theoretical amount: 33.97 g); yield: 79.5%.

[0068] Example 9 Preparation of Lafutidine

[0069]

[0070] Add 600g of ethyl acetate to the reaction bottle, add 72g (232.8mmol) of LAF-SM2, cool to below 10°C, add 60g (229.6mmol) of LAF-01; under stirring, naturally return to 25-30°C, react for 12-15hr; after the reaction is completed, add water, stand and separate; wash the organic phase with 5% sodium hydroxide aqueous solution three times (200g×3); dry with anhydrous sodium sulfate; filter, collect the filtrate, concentrate to dryness under reduced pressure, add 300g of ethanol, heat to dissolve, cool to crystallize, filter, collect the solid, and dry to obtain about 83g of lafutidine (theoretical amount: 99.07g); yield: 83.8%. Purity: 100.00%, dihydrolafutidine was not detected.

[0071] 1H-NMR (400Mz, DMSO-d6): 1.38~1.39ppm (m, 2H); 1.47~1.53ppm (m, 4H); 2.30~2.32ppm (m, 4H); 3.40ppm (s, 2H); 3.53~3.57ppm (dd, 1H); 3.72~3.75vppm (dd, 1H); 3.86~3.89ppm (t, 2H); 4.15~4.19ppm (dd, 1H); 4.33~4.37ppm (dd, 1H); 4.88~4.89ppm (d, 2H); 5.53~5.59ppm (m, 1H); 5.72~5.78ppm (m, 1H); 6.45~6.46ppm (dd, 1H); 6.49ppm (d, 1H); 6.71ppm (s, 1H); 6.91~6.93ppm (d, 1H); 7.69ppm (s, 1H); 8.07~8.08ppm (d, 1H); 8.50~8.53ppm (t, 1H).

[0072] Example 10 Preparation of Lafutidine

[0073]

[0074] Add 450g of tetrahydrofuran to the reaction bottle, add 45g (145.5mmol) of LAF-SM2, cool to below 10°C, add 37.5g (143.5mmol) of LAF-01; under stirring, naturally return to the temperature of 25-30°C, and react for 12-18hr; after the reaction is completed, add 450g of ethyl acetate, then add 600g of water, stand and separate the liquids; the separated organic phase is washed three times with 5% sodium hydroxide aqueous solution (200g×3); the organic phase is dried over anhydrous sodium sulfate; filter, collect the filtrate, concentrate under reduced pressure, add 200g of ethanol, heat to dissolve, cool and crystallize, filter, collect the solid, and dry; obtain about 55g (theoretical amount: 61.92g) of lafutidine; yield: 88.8%.

[0075] Comparative Example 1 Preparation of methanesulfonic acid 4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-butene-1-ol ester

[0076]

[0077] Add 600g of dichloromethane to the reaction bottle, add 100g (381.2mmol) of LAF-SM1-03, and cool to 0-5°C; add 50g (494.1mmol) of triethylamine, control the temperature not to exceed 10°C, and add 45g (401.6mmol) of methylsulfonyl chloride dropwise; after the addition is completed, keep warm at 15-25°C and stir to react for 30min; add 300g of water, stir and wash, stand and separate, and extract the aqueous phase with dichloromethane (150g×2); combine the organic phases, add anhydrous sodium sulfate to dry, filter, collect the filtrate, and concentrate under reduced pressure to dryness. The residue is LAF-SM1-04-Ms; the yield is 100%.

[0078] Comparative Example 2 Preparation of 2-[(2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-yl]-1H-isoindole-1,3(2H)-dione maleate

[0079]

[0080] Add 800g of acetonitrile to the reaction bottle, add LAF-SM1-04-Ms obtained in the previous step (theoretical amount 129.8g, 381.2mmol); add 5g (15.51mmol) of tetrabutylammonium bromide, add 106g (572.3mmol) of potassium phthalimide; after the addition, heat to 75-80°C, reflux reaction for about 18-24hr; cool to 15-25°C, filter to remove insoluble matter, collect the filtrate, concentrate under reduced pressure to dryness to obtain a residue, which is dissolved in 1000g of anhydrous ethanol; then add 58g (499.7mmol) of maleic acid, heat to reflux, cool to below 10°C for crystallization, filter, collect the solid, and dry to obtain about 128g (theoretical amount 193.5g) of LAF-SM1; yield: 71.3%.

[0081] Comparative Example 3 Preparation of Lafutidine

[0082]

[0083] Add 300g of anhydrous ethanol to the reaction bottle, add 25g (49.26mmol) of LAF-SM1, and add 20g (319.6mmol) of 80% hydrazine hydrate under stirring; heat to reflux and react for 4hr; after the reaction is completed, cool to 20-30°C; filter to remove insoluble matter, collect the filtrate, and concentrate to dryness under reduced pressure; add 150g of isopropyl ether to the residue and stir for about 1-2hr; filter out insoluble matter, and wash twice with 5% sodium hydroxide aqueous solution (50g×2); dry the organic phase with anhydrous sodium sulfate, filter, collect the filtrate, and concentrate to dryness under reduced pressure; the residue is obtained and 90g of tetrakis Dissolve in hydrofuran; cool to below 10°C, add 16g (51.73mmol) LAF-SM2; naturally return to 25-30°C, react for 12-15hr; after the reaction is complete, add 75g water, then add 120g ethyl acetate, stir and extract; stand and separate; wash the organic phase with 5% sodium hydroxide aqueous solution three times (50g×3); dry with anhydrous sodium sulfate; filter, collect the filtrate, concentrate to dryness under reduced pressure, add 80g ethanol, heat to dissolve, cool and crystallize, filter, collect the solid, dry to obtain about 16g of lafutidine (theoretical amount: 21.27g); yield: 75.3%. Purity: 99.251%, dihydrolafutidine 0.749%.

[0084] Comparative Example 4 Preparation of dihydrolafutidine

[0085]

[0086] Add 600g of anhydrous ethanol to the reaction bottle, add 50g (98.51mmol) of LAF-SM1, and add 60g (958.8mmol) of 80% hydrazine hydrate under stirring; heat to reflux and react for 10 hours; after the reaction is completed, cool to 20-30°C; filter to remove insoluble matter, collect the filtrate, and concentrate to dryness under reduced pressure; add 600g of isopropyl ether to the residue and stir for about 1-2 hours; filter out insoluble matter, and wash twice with 5% sodium hydroxide aqueous solution (100g×2); dry the organic phase with anhydrous sodium sulfate, filter, collect the filtrate, and reduce the pressure Concentrate to dryness; dissolve the residue with 500g tetrahydrofuran; cool to below 10°C, add 35g (113.2mmol) LAF-SM2; naturally warm to 25-30°C, react for 12-15hr; after the reaction is completed, add 400g water, then add 400g ethyl acetate, stir and extract; stand and separate; wash the organic phase with 5% sodium hydroxide aqueous solution three times (100g×3); dry with anhydrous sodium sulfate; filter, collect the filtrate, and concentrate to dryness under reduced pressure to obtain a residue of about 41g (theoretical amount: 42.5g); yield: 96.4%. Purity of Lafutidine: 95.766%, dihydrolafutidine 4.234%.

[0087] The 41g residue obtained above was separated by preparative liquid phase to obtain about 1.1g of dihydrolafutidine, of which 96.717% was dihydrolafutidine and 3.168% was lafutidine. The NMR data of dihydrolafutidine are as follows:

[0088] 1 H-NMR (400Mz, CDCl3): 1.37~1.39ppm (m, 2H); 1.48~1.51ppm (m, 4H); 1.54~1.58ppm (m, 2H); 1.68~1.75ppm (m, 2H); 2.29~2.31ppm (m, 4H); 3.13~3.18ppm (m, 2H); 3.39ppm (s, 2H); 3.52~3.55ppm (dd, 1H); 3.70~3.73ppm (dd , 1H); 4.14~4.18ppm (dd, 1H); 4.21~4.24ppm (t, 2H); 4.33~4.36ppm (dd, 1H); 6.45ppm (dd, 1H); 6.48~6.49ppm (m, 1H); 6.68ppm (s, 1H); 6.88~6.90ppm (d, 1H); 7.69ppm (s, 1H); 8.04~8.06ppm (d, 1H); 8.31~8.34ppm (t, 1H).

Claims

1. A method for preparing high-purity lafutidine, characterized in that: (1) Using the compound butene-1,4-diol compound LAF-SMA-S1 as the starting material, cyclizing with dichlorothionyl to obtain cyclic sulfenic acid lactone LAF-SMA-01; LAF-SMA-01 is then reacted with the bis-Boc-imide potassium salt compound LAF-SMA-S2 to obtain LAF-SMA-02; (2) Compound LAF-SMA-02 is reacted with compound LAF-SM1-01-X under alkaline conditions to obtain compound LAF-SMA; (3) Compound LAF-SMA is deprotected to obtain compound LAF-01; (4) Compound LAF-01 and compound LAF-SM2 are subjected to amine ester exchange reaction to obtain compound lafutidine; Among them, X=Cl, Br.

2. according to the method for preparing high-purity lafutidine described in claim 1, it is characterized in that: In step (1), the reagent used to activate thionyl chloride is imidazole or benzimidazole, and the amount of imidazole or benzimidazole is 0.95 to 1.05 times the molar amount of thionyl chloride; the amount of thionyl chloride is 1.0 to 1.3 times the molar amount of malein-1,4-diol; the solvent for the reaction of cyclic sulfinic acid lactone LAF-SMA-01 and bis-Boc-imide potassium is DMF or DMAc, and the amount of cyclic sulfinic acid lactone LAF-SMA-01 is 1.0 to 1.2 times the molar amount of bis-Boc-imide potassium salt.

3. The method for preparing high-purity lafutidine according to claim 1, wherein: The compound LAF-SM1-01-X used in step (2) is 2-chloro-4-(1-piperidinylmethyl)pyridine or 2-bromo-4-(1-piperidinylmethyl)pyridine; the reaction solvent is tetrahydrofuran, toluene, and dimethyl sulfoxide; the base used in the reaction is sodium hydride, potassium tert-butoxide, potassium hydroxide, and potassium carbonate; the reaction temperature is 60 to 120° C.; the amount of compound LAF-SMA-02 used is 1.0 to 1.4 times the molar amount of compound LAF-SM1-01-X used.

4. The method for preparing high-purity lafutidine according to claim 1, wherein: In step (3), LAF-01 is prepared by deprotection of LAF-SMA. The reagents used for deprotection are trifluoroacetic acid, hydrogen chloride, and methanesulfonic acid. The solvents used for the reaction are dichloromethane, ethyl acetate, and acetonitrile. The amount of the acid used for deprotection is 5.0 to 8.0 times the molar amount of the compound LAF-SMA.

5. The method for preparing high-purity lafutidine according to claim 1, wherein: In step (4), lafutidine is obtained by amine ester exchange reaction between LAF-01 and compound LAF-SM2. The solvents used in the reaction are ethyl acetate and tetrahydrofuran; the reaction temperature is 0-40° C.; and the recrystallization solvent of lafutidine is ethanol.

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