Industrial preparation method of pantoprazole intermediate pyridine hydrochloride

A technology of pyridine hydrochloride and pantoprazole, applied in the field of medicine, can solve the problems of high cost, unfavorable industrial production, low yield and the like, and achieve the effects of easy handling, low price and cost reduction

Inactive Publication Date: 2010-11-03

南京元德新材料科技有限公司

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AI-Extracted Technical Summary

Problems solved by technology

[0003] We know that 2-chloromethyl-3,4-lutidine hydrochloride is an important intermediate for the preparation of pantoprazole, and its preparation method is generally: use 2-methyl-3-hydroxypyridine as The raw materials are synthesized through seven steps of...

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Abstract

The invention discloses an industrial preparation method of pantoprazole intermediate pyridine hydrochloride, including the following steps: (1) preparation of 3-methoxy-2-methyl-4H-pyran-4-ketone; (2) preparation of 3-methoxy-2-methyl-4(1H)-pyridone; (3) preparation of 4-chlorine-3-methoxy-2-methylpyridine; (4) preparation of 4-chlorine-3-methoxy-2-methylpyridine-N-oxide; (5) preparation of 3, 4-dimethoxy-2-methylpridine-N-oxide; (6) preparation of 2-hydroxymethyl-3, 4-dimethoxyprindine; (7) preparation of 2-chloromethyl-3, 4-dimethxyl pyridine hydrochloride. In the invention, the reactions in the steps are all carried out under atmospheric pressure while temperature is lower than 100 DEG C, condition is mild, thus being safe and reliable; besides, the raw materials adopted in the invention are all low in price and high in utilization ratio, and multiple raw materials can be used repeatedly, thus reducing cost; and the quality of the obtained product can reach more than 98%, thus completely meeting the requirement; in addition, waste gas and waste water which are produced in the steps are easy to be treated, thus being applicable to industrialized production.

Application Domain

Organic chemistry

Technology Topic

DimethpyrindeneKetone +10

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Examples

Experimental program(3)

Example Embodiment

[0026] Example 1:

[0027] (1) Preparation of 3-methoxy-2-methyl-4H-pyran-4-one

[0028] Dissolve 140g of sodium hydroxide in 250g of water, then add 141g of maltol, stir to dissolve, heat to 84°C, slowly add 19g of dimethyl sulfate dropwise, and control the temperature at 84~85°C, and use 30 % Sodium hydroxide solution adjusts the pH value to be maintained at about 11. After the dripping is completed, the temperature is raised to 96°C, kept for 13 hours, and the temperature is lowered to below 30°C to obtain 130g of orange-yellow liquid of 3-methoxy-2-methyl-4H-pyridine Pyran-4one;

[0029] (2) Preparation of 3-methoxy-2-methyl-4(1H)-pyridone

[0030] Add 140g of 3-methoxy-2-methyl-4H-pyran-4one to 1700g of ammonia water, stir at 85°C for 16 hours, and then evaporate under reduced pressure to remove water and dry to obtain 130g of finished product as a brown-yellow solid 3-methoxy- 2-Methyl-4(1H)-pyridone, the yield is 93%;

[0031] (3) Preparation of 4-chloro-3-methoxy-2-methylpyridine

[0032] Put 139g 3-methoxy-2-methyl-4(1H)-pyridone into 2500g phosphorus oxychloride, heat to 88°C and reflux to dissolve, adjust the pH to 5 with 30% sodium hydroxide solution, and then It was extracted with dichloromethane three times, the extracts were combined, and the dichloromethane was evaporated under reduced pressure to obtain 125 g of 4-chloro-3-methoxy-2-methylpyridine as a brown liquid with a yield of 79%.

[0033] (4) Preparation of 4-chloro-3-methoxy-2-methylpyridine-N-oxide

[0034] Put 157.5g 4-chloro-3-methoxy-2-methylpyridine into 30% sodium hydroxide solution, raise the temperature to 87°C to dissolve, drop 560g hydrogen peroxide into it, keep it at 68°C for 16 hours, and cool to Extract with methylene chloride below 30°C for 3 to 4 times, combine the extracts and evaporate the solvent to obtain 160 g of 4-chloro-3-methoxy-2-methylpyridine-N-oxide as a pale yellow solid, with a yield of 92%;

[0035] (5) Preparation of 3,4-Dimethoxy-2-methylpyridine-N-oxide

[0036] To 173.5g of 4-chloro-3-methoxy-2-methylpyridine-N-oxide, add 160g of sodium hydroxide, add dichloromethane and stir to dissolve, heat up to 88℃, reflux for 16 hours, filter to remove the salt , The filtrate was evaporated to remove the solvent, the residue was added with methanol, the extracts were combined and evaporated to remove the solvent, and the temperature was lowered to obtain 148g of light yellow solid 3,4-dimethoxy-2-methylpyridine-N-oxide, with a yield of 88%;

[0037] (6) Preparation of 2-hydroxymethyl-3,4-dimethoxypyridine

[0038] To 169g of 3,4-dimethoxy-2-methylpyridine-N-oxide, add 1900g of acetic anhydride and increase the temperature to 59°C for 16 hours, distill off the acetic anhydride, and add 30% sodium hydroxide solution to the residue to adjust The pH is 9, 68°C for 2 hours, the temperature is lowered to 30°C, and the mixture is extracted with dichloromethane for 3 to 4 times. The extracts are combined, and the extracts are evaporated to remove the solvent to obtain brown-yellow solid 2-hydroxymethyl-3,4- Dimethoxypyridine 143g, yield 85%;

[0039] (7) Preparation of 2-chloromethyl-3,4-lutidine hydrochloride

[0040] Dissolve 169g of 2-hydroxymethyl-3,4-dimethoxypyridine with 1850g of dichloromethane, lower the temperature to below -5°C, add thionyl chloride dropwise, the temperature does not exceed 0°C, and stir for 4 hours after the addition Add 1500g of ethanol and increase the temperature to 87°C, lower the temperature to below 25°C, spin and filter to dryness with a centrifuge, and dry to obtain white crystals of 2-chloromethyl-3,4-lutidine hydrochloride 185g, the yield is 82% .

Example Embodiment

[0041] Example 2:

[0042] (1) Preparation of 3-methoxy-2-methyl-4H-pyran-4-one

[0043] Dissolve 230g of sodium hydroxide in 410g of water, then add 231g of maltol, stir to dissolve, heat up to 84℃, slowly add 312g of dimethyl sulfate dropwise, the temperature of the drop is controlled at 80°C, and 30% hydrogen is used at the end of the drop Adjust the pH value of the sodium oxide solution to keep around 11, after the dropping, the temperature is raised to 92°C, kept for 13 hours, and the temperature is lowered to below 30°C to obtain 210g of orange-yellow liquid 3-methoxy-2-methyl-4H-pyran -4 Ketones;

[0044] (2) Preparation of 3-methoxy-2-methyl-4(1H)-pyridone

[0045] Add 210g of 3-methoxy-2-methyl-4H-pyran-4one to 2550g of ammonia, stir at 80°C for 16 hours, and then evaporate under reduced pressure to remove water and dry to obtain the finished product 198g of brown-yellow solid 3-methoxy -2-Methyl-4(1H)-pyridone, the yield is 93.9%;

[0046] (3) Preparation of 4-chloro-3-methoxy-2-methylpyridine

[0047] Put 180g of 3-methoxy-2-methyl-4(1H)-pyridone into 3240g of phosphorus oxychloride, heat to 80°C and reflux to dissolve, adjust the pH to 5 with 30% sodium hydroxide solution, It was extracted with dichloromethane three times, the extracts were combined, and the dichloromethane was evaporated under reduced pressure to obtain 140 g of brown liquid 4-chloro-3-methoxy-2-methylpyridine with a yield of 77.9%.

[0048] (4) Preparation of 4-chloro-3-methoxy-2-methylpyridine-N-oxide

[0049] Put 140g 4-chloro-3-methoxy-2-methylpyridine into 280g 30% sodium hydroxide solution, raise the temperature to 85℃ to dissolve, drop 500g hydrogen peroxide into it, keep it at 65℃ for 16 hours, and cool down Use dichloromethane to extract 3 to 4 times below 30°C, combine the extracts and evaporate the solvent to obtain 129 g of 4-chloro-3-methoxy-2-methylpyridine-N-oxide, with a yield of 92.7% ;

[0050] (5) Preparation of 3,4-Dimethoxy-2-methylpyridine-N-oxide

[0051] To 150g of 4-chloro-3-methoxy-2-methylpyridine-N-oxide, add 145g of sodium hydroxide, add 750g of dichloromethane and stir to dissolve, heat up to 88℃, reflux and keep for 16 hours, filter out Salt, the filtrate was evaporated to remove the solvent, the residue was added with methanol, the extracts were combined and evaporated to remove the solvent, and the temperature was lowered to obtain 130 g of light yellow solid 3,4-dimethoxy-2-methylpyridine-N-oxide with a yield of 86.7%;

[0052] (6) Preparation of 2-hydroxymethyl-3,4-dimethoxypyridine

[0053] To 190g of 3,4-dimethoxy-2-methylpyridine-N-oxide, add 1900g of acetic anhydride and increase the temperature to 50°C for 16 hours, distill off the acetic anhydride, and add 30% sodium hydroxide solution to the residue Adjust the pH to 9, keep the temperature at 65°C for 2 hours, lower the temperature to below 30°C, extract 3 to 4 times with dichloromethane, combine the extracts, and evaporate the solvent to obtain brown-yellow solid 2-hydroxymethyl-3,4 -Dimethoxypyridine 162g, yield 85%;

[0054] (7) Preparation of 2-chloromethyl-3,4-lutidine hydrochloride

[0055] Dissolve 140g of 2-hydroxymethyl-3,4-dimethoxypyridine with 1450g of dichloromethane, lower the temperature to below -5°C, add 280g of thionyl chloride dropwise, the temperature does not exceed 0°C, and stir after the addition After 4 hours, add 1250g of ethanol and raise the temperature to 85°C, lower the temperature to below 25°C, spin and filter to dryness with a centrifuge, and dry to obtain 116g of white crystal 2-chloromethyl-3,4-lutidine hydrochloride. The yield is 82.7%.

Example Embodiment

[0056] Example 3:

[0057] (1) Preparation of 3-methoxy-2-methyl-4H-pyran-4-one

[0058] Dissolve 160g of sodium hydroxide in 285g of water, add 159g of maltol, stir to dissolve, heat to 86°C, slowly add 218g of dimethyl sulfate dropwise, the temperature of the drop is controlled at 85°C, and 30% hydrogen is used in the later stage of the drop Adjust the pH value of the sodium oxide solution to keep around 11, after the dripping, the temperature is raised to 96°C, kept for 13 hours, and the temperature is lowered to below 30°C to obtain 148g of orange-yellow liquid 3-methoxy-2-methyl-4H-pyran -4 Ketones;

[0059] (2) Preparation of 3-methoxy-2-methyl-4(1H)-pyridone

[0060] Add 175g of 3-methoxy-2-methyl-4H-pyran-4one to 2100g of ammonia, stir at 85°C for 16 hours, and then evaporate under reduced pressure to remove water and dry to obtain the finished product 164g of brown solid 3-methoxy -2-Methyl-4(1H)-pyridone, the yield is 93.5%;

[0061] (3) Preparation of 4-chloro-3-methoxy-2-methylpyridine

[0062] Put 125g of 3-methoxy-2-methyl-4(1H)-pyridone into 2250g of phosphorus oxychloride, heat to 90°C and reflux to dissolve, adjust the pH to 5 with 30% sodium hydroxide solution, It was extracted 3 times with dichloromethane, the extracts were combined, and the dichloromethane was evaporated under reduced pressure to obtain 99 g of brown liquid 4-chloro-3-methoxy-2-methylpyridine with a yield of 77.4%.

[0063] (4) Preparation of 4-chloro-3-methoxy-2-methylpyridine-N-oxide

[0064] Put 120g 4-chloro-3-methoxy-2-methylpyridine into 240g 30% sodium hydroxide solution, heat up to 90℃ to dissolve, drop 420g hydrogen peroxide into it, keep at 70℃ for 16 hours, and cool down Use dichloromethane to extract 3 to 4 times below 30°C, combine the extracts and evaporate the solvent to obtain 110 g of 4-chloro-3-methoxy-2-methylpyridine-N-oxide with a yield of 92% ;

[0065] (5) Preparation of 3,4-Dimethoxy-2-methylpyridine-N-oxide

[0066] To 175g of 4-chloro-3-methoxy-2-methylpyridine-N-oxide, add 175g of sodium hydroxide, add 875g of dichloromethane and stir to dissolve, heat up to 90℃, reflux and keep for 16 hours, filter out Salt, the filtrate was evaporated to remove the solvent, the residue was added with methanol, the extracts were combined and evaporated to remove the solvent, and the temperature was lowered to obtain 154 g of light yellow solid 3,4-dimethoxy-2-methylpyridine-N-oxide, with a yield of 89%;

[0067] (6) Preparation of 2-hydroxymethyl-3,4-dimethoxypyridine

[0068] To 210g of 3,4-dimethoxy-2-methylpyridine-N-oxide, add 2100g of acetic anhydride and increase the temperature to 60°C for 16 hours, distill off the acetic anhydride, and add 30% sodium hydroxide solution to the residue Adjust the pH to 9, keep the temperature at 70℃ for 2 hours, lower the temperature to below 30℃, extract 3 to 4 times with dichloromethane, combine the extracts, and evaporate the solvent to obtain brown-yellow solid 2-hydroxymethyl-3,4 -Dimethoxypyridine 179g, yield 85%;

[0069] (7) Preparation of 2-chloromethyl-3,4-lutidine hydrochloride

[0070] Dissolve 155g of 2-hydroxymethyl-3,4-dimethoxypyridine with 1550g of dichloromethane, lower the temperature to below -5°C, add 310g of thionyl chloride dropwise, the temperature does not exceed 0°C, and stir after the addition For 4 hours, add 1375g of ethanol and raise the temperature to 90℃, then lower the temperature to below 25℃, filter to dryness with a centrifuge, and dry to obtain 127g of white crystals of 2-chloromethyl-3,4-lutidine hydrochloride. The yield was 83.2%.

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Classification and recommendation of technical efficacy words

Low price
Mild conditions

Industrial preparation method of pantoprazole intermediate pyridine hydrochloride

A technology of pyridine hydrochloride and pantoprazole, applied in the field of medicine, can solve the problems of high cost, unfavorable industrial production, low yield and the like, and achieve the effects of easy handling, low price and cost reduction

AI-Extracted Technical Summary

Problems solved by technology

Abstract

Image

Examples

Example Embodiment

Example Embodiment

Example Embodiment

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Description & Claims & Application Information

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