CN117186067A - Method for preparing lafutidine key intermediate - Google Patents
Method for preparing lafutidine key intermediate Download PDFInfo
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- CN117186067A CN117186067A CN202311123755.6A CN202311123755A CN117186067A CN 117186067 A CN117186067 A CN 117186067A CN 202311123755 A CN202311123755 A CN 202311123755A CN 117186067 A CN117186067 A CN 117186067A
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- lafutidine
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- key intermediate
- preparing
- piperidine
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- KMZQAVXSMUKBPD-DJWKRKHSSA-N Lafutidine Chemical compound C=1C=COC=1C[S+]([O-])CC(=O)NC\C=C/COC(N=CC=1)=CC=1CN1CCCCC1 KMZQAVXSMUKBPD-DJWKRKHSSA-N 0.000 title claims abstract description 34
- 229960003303 lafutidine Drugs 0.000 title claims abstract description 34
- 238000000034 method Methods 0.000 title claims abstract description 31
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims abstract description 60
- 238000006243 chemical reaction Methods 0.000 claims abstract description 57
- QXCABBOLSRZFTK-UHFFFAOYSA-N (2-chloropyridin-4-yl)-piperidin-1-ylmethanone Chemical compound C1=NC(Cl)=CC(C(=O)N2CCCCC2)=C1 QXCABBOLSRZFTK-UHFFFAOYSA-N 0.000 claims abstract description 24
- QXCOHSRHFCHCHN-UHFFFAOYSA-N 2-chloropyridine-4-carboxylic acid Chemical compound OC(=O)C1=CC=NC(Cl)=C1 QXCOHSRHFCHCHN-UHFFFAOYSA-N 0.000 claims abstract description 23
- FCGXHPOYGAGSIQ-UHFFFAOYSA-N 2-chloro-4-(piperidin-1-ylmethyl)pyridine Chemical compound C1=NC(Cl)=CC(CN2CCCCC2)=C1 FCGXHPOYGAGSIQ-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000004519 manufacturing process Methods 0.000 claims abstract description 20
- 238000006722 reduction reaction Methods 0.000 claims abstract description 15
- 150000001263 acyl chlorides Chemical class 0.000 claims abstract description 14
- 230000010933 acylation Effects 0.000 claims abstract description 14
- 238000005917 acylation reaction Methods 0.000 claims abstract description 14
- 230000009467 reduction Effects 0.000 claims abstract description 6
- 239000007858 starting material Substances 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 61
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 238000000605 extraction Methods 0.000 claims description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- 239000012044 organic layer Substances 0.000 claims description 20
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- 239000012279 sodium borohydride Substances 0.000 claims description 15
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 239000011259 mixed solution Substances 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 238000012805 post-processing Methods 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 10
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 238000003756 stirring Methods 0.000 description 16
- 238000007792 addition Methods 0.000 description 13
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- 238000005070 sampling Methods 0.000 description 8
- 238000000926 separation method Methods 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 6
- 230000008033 biological extinction Effects 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 238000005660 chlorination reaction Methods 0.000 description 4
- 230000001276 controlling effect Effects 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 230000006837 decompression Effects 0.000 description 3
- 230000032798 delamination Effects 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 239000011592 zinc chloride Substances 0.000 description 3
- 235000005074 zinc chloride Nutrition 0.000 description 3
- UDDVPFLXGOBESH-UHFFFAOYSA-N (2-chloropyridin-4-yl)methanol Chemical compound OCC1=CC=NC(Cl)=C1 UDDVPFLXGOBESH-UHFFFAOYSA-N 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000006053 organic reaction Methods 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- ORLGLBZRQYOWNA-UHFFFAOYSA-N 4-methylpyridin-2-amine Chemical compound CC1=CC=NC(N)=C1 ORLGLBZRQYOWNA-UHFFFAOYSA-N 0.000 description 1
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 229940122957 Histamine H2 receptor antagonist Drugs 0.000 description 1
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- -1 acyl imidazole Chemical compound 0.000 description 1
- 229950011175 aminopicoline Drugs 0.000 description 1
- 239000003699 antiulcer agent Substances 0.000 description 1
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 239000003485 histamine H2 receptor antagonist Substances 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Landscapes
- Hydrogenated Pyridines (AREA)
Abstract
The invention discloses a method for preparing a lafutidine key intermediate, which belongs to the technical field of organic synthesis and comprises the following steps: (1) acylation: 2-chloroisonicotinic acid is taken as a starting material, and acyl chloride is prepared through acylation; (2) reaction with piperidine: reacting acyl chloride with piperidine to obtain (2-chloropyridin-4-yl) -piperidin-1-yl-methanone; (3) reduction reaction: reduction of (2-chloropyridin-4-yl) -piperidin-1-yl-methanone gives lafutidine key intermediate 2-chloro-4- (1-piperidylmethyl) pyridine. The acyl chloride obtained in the step (1) of the method directly performs the reaction of the step (2) without any treatment, so that only two steps of reactions are performed in actual operation. The method shortens the working procedure and simplifies the production route. The yield of the target product obtained by the method is more than 80%, and meanwhile, the source of the initial raw material 2-chloroisonicotinic acid is wide, the price is low, and the production cost is greatly reduced.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a method for preparing a key intermediate of lafutidine.
Background
Lafutidine is an antiulcer drug for gastric ulcer and duodenal ulcer, and is prepared by the combined development of Fujirebio company and large Taiho company, and the product belongs to a second-generation histamine H2 receptor antagonist, can inhibit gastric acid secretion, plays a role in protecting stomach, and is marketed in month 4 of 2000 under the trade name of Storga, protecadin.
In recent years, as the market share and market share of lafutidine are rapidly increased due to the excellent curative effect of lafutidine, the demand for raw material medicines of lafutidine is also increasing, and 2-chloro-4- (1-piperidylmethyl) pyridine has wide market prospect as a key intermediate of lafutidine, and various methods are also available for synthesizing 2-chloro-4- (1-piperidylmethyl) pyridine, such as:
the method comprises the following steps:
the method is from KR2022/133645,2022, A, the preparation route is long, four steps of reaction are needed, 2-chloroisonicotinic acid is reduced by sodium borohydride through esterification, and the product is obtained by reacting with piperidine after chlorination, wherein the esterification and reduction reaction time is long. The method has long route and more reaction steps, so the yield is lower.
The improved method based on this is from document WO2008/74752,2008, a2, and uses N, N-Carbonyl Diimidazole (CDI) to react with 2-chloroisonicotinic acid in a condensation way to form acyl imidazole with higher activity, and then directly uses sodium borohydride to reduce, so that the reduction time is greatly shortened. But the material cost is higher.
The second method is as follows:
the method is from documents EP1741703,2007 and A1 and WO2010/7374 and 2010 and A1, 2-chloroisonicotinic acid is directly reduced to obtain an intermediate (2-chloro-4-pyridyl) methanol, and then the intermediate (2-chloro-4-pyridyl) methanol is subjected to chlorination and piperidine reaction to obtain a target product. The route shortens the steps and reduces the working procedures. However, the reagents for directly reducing carboxylic acid are borane dimethyl sulfide or sodium borohydride and boron trifluoride diethyl ether, the cost of the reagents is high, and the reaction time is long.
And a third method:
the method is from document CN 10230482B, takes 2-amino-4-methylpyridine as a raw material, carries out diazotization and chlorination, then carries out chlorination by using a free radical initiator, and finally reacts with piperidine to obtain a target product. Although the reaction step is shortened, the total yield is still lower and is only 32%; and the solvent carbon tetrachloride used in the second step has great harm to the ozone layer and aquatic organisms.
Therefore, how to shorten the reaction time, improve the yield of the target product and reduce the production cost is a difficult point for preparing the key intermediate 2-chloro-4- (1-piperidylmethyl) pyridine of lafutidine.
Disclosure of Invention
The invention aims to provide a method for preparing a lafutidine key intermediate, which aims to solve the technical problems in the background technology.
In order to achieve the above purpose, the invention discloses a method for preparing a key intermediate of lafutidine, which comprises the following steps:
(1) Acylation: 2-chloroisonicotinic acid is taken as a starting material, and acyl chloride is prepared through acylation;
(2) Reaction with piperidine: reacting acyl chloride with piperidine to obtain (2-chloropyridin-4-yl) -piperidin-1-yl-methanone;
(3) Reduction reaction: reduction of (2-chloropyridin-4-yl) -piperidin-1-yl-methanone gives lafutidine key intermediate 2-chloro-4- (1-piperidylmethyl) pyridine.
Further, in the step (1), thionyl chloride is added to carry out acylation.
Further, in the step (1), when the consumption of the 2-chloroisonicotinic acid is detected to be less than 1%, the reaction is ended, and then piperidine is directly added into a reaction system without post-treatment, so that the reaction in the step (2) is carried out.
In the step (2), piperidine is first dissolved in organic solvent to prepare mixed liquid, and the mixed liquid is then added into the reaction system to react.
Further, after the step (2) is completed, a post-processing operation is required: adding water into the reaction system for extraction, adding an organic solvent for extraction, standing for extraction, taking an organic layer, adding water into the organic layer for washing, and concentrating the organic layer under reduced pressure to obtain (2-chloropyridin-4-yl) -piperidin-1-yl-methanone.
Further, in the step (3), the reduction is performed with sodium borohydride.
Further, the sodium borohydride is added in portions.
Further, in the step (3), when the consumption of (2-chloropyridin-4-yl) -piperidin-1-yl-methanone is detected to be less than 1%, the reaction is stopped and the post-treatment is performed: adding water into the reaction system for extraction, adding HCl to adjust the pH value to 6-7, then concentrating under reduced pressure, adding an organic solvent for extraction, concentrating under reduced pressure and distilling under reduced pressure the extracted organic layer to obtain the target product 2-chloro-4- (1-piperidylmethyl) pyridine.
Further, in the preparation process, the molar ratio of the 2-chloroisonicotinic acid, the thionyl chloride, the piperidine and the sodium borohydride is 1:1-1.5:1-1.5:0.8-1.0. In the invention, compared with 2-chloroisonicotinic acid, the addition amount of sulfoxide chloride and piperidine is slightly excessive, and the addition amount of sodium borohydride is slightly insufficient, which is designed based on the progress of the organic reaction, so that the organic reaction can be promoted to be carried out more smoothly.
Further, the preparation process is carried out in an organic system, wherein the organic solvent comprises one or a mixture of several of toluene, xylene, methylene dichloride, methanol, ethanol and N, N-dimethylformamide.
Compared with the prior art, the method for preparing the lafutidine key intermediate has the following advantages: the acid chloride obtained in the step (1) is directly subjected to the reaction of the step (2) without any treatment, so that only two steps of reactions are carried out in actual operation. The method shortens the working procedure and simplifies the production route. The yield of the target product obtained by the method is more than 80%, and meanwhile, the source of the initial raw material 2-chloroisonicotinic acid is wide, the price is low, and the production cost is greatly reduced.
Drawings
Fig. 1: the invention relates to a process flow chart of a method for preparing a lafutidine key intermediate.
Detailed Description
Embodiments of the present invention will now be described in detail with reference to the following examples, which are provided for illustration only and are not to be construed as limiting the scope of the invention. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer.
A process for preparing a key intermediate of lafutidine comprising the steps of:
(1) Acylation: 2-chloroisonicotinic acid is taken as a starting material, and acyl chloride is prepared through acylation;
(2) Reaction with piperidine: reacting acyl chloride with piperidine to obtain (2-chloropyridin-4-yl) -piperidin-1-yl-methanone;
(3) Reduction reaction: and (3) reducing the product (2-chloropyridin-4-yl) -piperidin-1-yl-methanone of the step (2) by using sodium borohydride as a reducing agent to obtain the target product 2-chloro-4- (1-piperidylmethyl) pyridine.
Wherein, the acyl chloride obtained in the step (1) directly carries out the reaction of the step (2) without any treatment, so that only two steps of reactions are carried out in actual operation. The method shortens the working procedure and simplifies the production route. The yield of the target product obtained by the method is more than 80%, and meanwhile, the source of the initial raw material 2-chloroisonicotinic acid is wide, the price is low, and the production cost is greatly reduced.
Example 1
The preparation of the key intermediate 2-chloro-4- (1-piperidylmethyl) pyridine of lafutidine comprises the following steps:
(1) Acylation and reaction with piperidine:
into a 1000mL four-necked flask, 200g (1.27 mol,1.0 eq) of 2-chloroisonicotinic acid and 400mL of methylene chloride were charged, and 9.3g (0.127 mol,0.1 eq) of N, N-dimethylformamide was added thereto after stirring and suspending. Then, the temperature was raised to 35-40 ℃ (reflux), and 181g (1.52 mol,1.2 eq) of thionyl chloride was added thereto, followed by completion of the addition over about 2 hours.
And (3) carrying out heat preservation reaction for 7 hours until the system is dissolved, sampling and detecting that the consumption of the raw material 2-chloroisonicotinic acid is less than 1%, and stopping the reaction. Then decompressing and desolventizing to obtain yellow oily matter, namely the acyl chloride.
Then 250mL of dichloromethane is added into the four-neck flask, after stirring and dissolution, the temperature of the system is controlled to be 0-10 ℃, and then dichloromethane mixed solution of piperidine and triethylamine is added dropwise, wherein the mixed solution comprises the following components: piperidine 130g (1.52 mol,1.2 eq), triethylamine 167g (1.65 mol,1.3 eq), dichloromethane 150mL; after the addition, the cold bath is removed, the temperature is returned to 25-30 ℃ at room temperature, and the reaction is stopped after 10 hours of reaction.
And then post-treatment: adding 200mL of water into a four-neck flask for extraction and extinction, stirring, dissolving, standing and layering, adding 200mL of dichloromethane into a water layer for extraction, standing and layering, combining organic layers, and then adding 200mL of water for washing; standing and layering again, and concentrating the organic layer under reduced pressure to obtain 270g of (2-chloropyridin-4-yl) -piperidin-1-yl-methanone, wherein the crude product yield is 94.62% and the purity is 99.05%.
(2) Reduction reaction: 200g of (2-chloropyridin-4-yl) -piperidin-1-yl-methanone obtained in the step (1) was taken and put into a 1000mL four-necked flask, to which 600mL of methanol and 61.74g (0.56 mol,0.5 eq) of calcium chloride were added, and the solution was stirred. Then controlling the temperature to 20-30 ℃, adding 37.83g (1.0 mol,0.9 eq) sodium borohydride powder in batches, keeping the temperature for 2 hours after the addition, sampling and monitoring that the consumption of (2-chloropyridin-4-yl) -piperidin-1-yl-methanone is less than 1%, and stopping the reaction.
200mL of ice water is added into the reaction system for extraction and extinction at the temperature of 20-30 ℃, and 65g of 6N HCl is added into the reaction system for regulating the pH value to 6-7. After stirring for 0.5h and retesting the pH, the methanol is removed by decompression concentration. Then 200ml of x 2 dichloromethane was added thereto for extraction, and the mixture was allowed to stand for separation. The organic layer was concentrated under reduced pressure to give 220g of crude 2-chloro-4- (1-piperidylmethyl) pyridine. The crude product is distilled under reduced pressure to obtain 210g of light yellow oily substance, namely pure 2-chloro-4- (1-piperidylmethyl) pyridine. The yield was 89.80% and the purity was 99.50%.
Example 2
The preparation of the key intermediate 2-chloro-4- (1-piperidylmethyl) pyridine of lafutidine comprises the following steps:
(1) Acylation and reaction with piperidine:
into a 1000mL four-necked flask, 200g (1.27 mol,1.0 eq) of 2-chloroisonicotinic acid and 400mL of methylene chloride were charged, and after stirring and suspending, 9.3g (0.127 mol,0.1 eq) of N, N-dimethylformamide was added. Then, the temperature was raised to 35 to 40℃and 181g (1.52 mol,1.2 eq) of thionyl chloride was added dropwise thereto, after which the addition was completed for about 2 hours.
Then, the reaction is carried out for 7 hours until the system is dissolved, the consumption of the raw material 2-chloroisonicotinic acid is detected to be less than 1% by sampling, and the reaction is stopped. Then decompressing and desolventizing to obtain yellow oily matter, namely the acyl chloride.
250mL of fresh methylene chloride was added thereto, and the mixture was dissolved by stirring. Controlling the temperature to be 0-10 ℃, and dropwise adding a dichloromethane mixed solution of piperidine and N, N-diisopropylethylamine into the mixed solution, wherein the mixed solution comprises the following components: 130g (1.52 mol,1.2 eq) piperidine and 213g (1.65 mol1.3 eq) N, N-diisopropylethylamine, and 150mL dichloromethane. After the addition, the cold bath was removed, the temperature was returned to room temperature (25-30 ℃ C.), and the reaction was stopped for 10 hours.
And then post-treatment: to this, 200mL of water was added for extraction, and after stirring to dissolve the solution, the solution was allowed to stand for separation, and the aqueous layer was extracted with 200mL of dichloromethane. After standing and delamination, the organic layers were combined and washed with 200mL of water. After standing and layering, the organic layer was concentrated under reduced pressure to give 275g of (2-chloropyridin-4-yl) -piperidin-1-yl-methanone in a crude yield of 96.38% and a purity of 99.1%.
(2) Reduction reaction: 200g (1.11 mol,1.0 eq) of the crude (2-chloropyridin-4-yl) -piperidin-1-yl-methanone obtained in step (1) was taken and placed in a 1000mL four-necked flask, to which 600mL of methanol and 76.33g (0.56 mol,0.5 eq) of zinc chloride were added and the solution was stirred.
The temperature was controlled at 20-30℃and 37.83g (1.0 mol,0.9 eq) of sodium borohydride powder was added thereto in portions, the temperature was kept for 2 hours after the addition, and the reaction was stopped by sampling and monitoring that (2-chloropyridin-4-yl) -piperidin-1-yl-methanone was consumed to less than 1%. 200mL of ice water is added into the reaction system for extraction and extinction at the temperature of 20-30 ℃, and 65g of 6N HCl is added into the reaction system for regulating the pH value to 6-7. After stirring for 0.5h and retesting the pH, the methanol is removed by decompression concentration. Then 200ml of x 2 dichloromethane was added thereto for extraction, and the mixture was allowed to stand for separation. The organic layer was concentrated under reduced pressure to give 230g of crude 2-chloro-4- (1-piperidylmethyl) pyridine. The crude product is distilled under reduced pressure to obtain 218g of light yellow oily matter, namely the pure 2-chloro-4- (1-piperidylmethyl) pyridine. Yield 93.21% and purity 99.30%.
Example 3
The preparation of the key intermediate 2-chloro-4- (1-piperidylmethyl) pyridine of lafutidine comprises the following steps:
(1) Acylation and reaction with piperidine:
into a 1000mL four-necked flask, 200g (1.27 mol,1.0 eq) of 2-chloroisonicotinic acid and 400mL of toluene were charged and suspended with stirring. Subsequently, the temperature was raised to 65 to 70℃and 181g (1.52 mol,1.2 eq) of thionyl chloride was added dropwise thereto over a period of about 2 hours. Then, the reaction is carried out for 10 hours until the system is dissolved, the consumption of the raw material 2-chloroisonicotinic acid is detected to be less than 1% by sampling, and the reaction is stopped. Then decompressing and desolventizing to obtain deep yellow oily matter, namely the acyl chloride.
250mL of fresh toluene was added thereto, and the mixture was dissolved by stirring. Controlling the temperature to be 0-10 ℃, and dropwise adding toluene mixed solution of piperidine and N, N-diisopropylethylamine into the mixed solution, wherein the mixed solution comprises the following components: 130g (1.52 mol,1.2 eq) piperidine and 213g (1.65 mol,1.3 eq) N, N-diisopropylethylamine, and 150mL toluene. After the addition, the cold bath is removed, the temperature is returned to room temperature (25-30 ℃), and the reaction is stopped for 10 hours.
And then post-treatment: 200mL of water was added thereto for extraction, the mixture was stirred to dissolve the residue, and the mixture was allowed to stand still for separation, and 200mL of toluene was added to the aqueous layer for extraction. After standing and delamination, the organic layers were combined and washed with 200mL of water. After standing and layering, the organic layer was concentrated under reduced pressure to give 265g of (2-chloropyridin-4-yl) -piperidin-1-yl-methanone in a crude yield of 92.87% and a purity of 99.0%.
(2) Reduction reaction: 200g (1.11 mol,1.0 eq) of the crude (2-chloropyridin-4-yl) -piperidin-1-yl-methanone produced in step (1) was taken and placed in a 1000mL four-necked flask, to which 600mL of methanol and 76.33g (0.56 mol,0.5 eq) of zinc chloride were added and dissolved with stirring. The temperature is controlled at 20-30 ℃, 37.83g (1.0 mol,0.9 eq) sodium borohydride powder is added in batches, the temperature is kept for 5 hours after the addition, and the reaction is stopped after sampling and monitoring that the consumption of (2-chloropyridin-4-yl) -piperidin-1-yl-methanone is less than 1 percent. 200mL of ice water is added into the reaction system for extraction and extinction at the temperature of 20-30 ℃, and 65g of 6N HCl is added into the reaction system for regulating the pH value to 6-7. After stirring for 0.5h and retesting the pH, the methanol is removed by decompression concentration. Then 200ml of x 2 dichloromethane was added thereto for extraction, and the mixture was allowed to stand for separation. The organic layer was concentrated under reduced pressure to give 215g of crude 2-chloro-4- (1-piperidylmethyl) pyridine. The crude product is distilled under reduced pressure to obtain 215g of light yellow oily matter, namely the pure 2-chloro-4- (1-piperidylmethyl) pyridine. Yield 91.92% and purity 99.10%.
Example 4
The preparation of the key intermediate 2-chloro-4- (1-piperidylmethyl) pyridine of lafutidine comprises the following steps:
(1) Acylation and reaction with piperidine: into a 1000mL four-necked flask, 200g (1.27 mol,1.0 eq) of 2-chloroisonicotinic acid and 400mL of methylene chloride were charged, and after stirring and suspending, 9.3g (0.127 mol,0.1 eq) of N, N-dimethylformamide was added. Then, the temperature was raised to 35 to 40℃and 181g (1.52 mol,1.2 eq) of thionyl chloride was added dropwise thereto, after which the addition was completed for about 2 hours. Then, the reaction is carried out for 7 hours until the system is dissolved, the consumption of the raw material 2-chloroisonicotinic acid is detected to be less than 1% by sampling, and the reaction is stopped. Then decompressing and desolventizing to obtain yellow oily matter, namely the acyl chloride.
250mL of fresh methylene chloride was added thereto, and the mixture was dissolved by stirring. Controlling the temperature to be 0-10 ℃, and dropwise adding dichloromethane mixed solution of piperidine and N, N-diisopropylethylamine into the mixed solution, wherein the mixed solution comprises the following components: 130g (1.52 mol of 1.2 eq) piperidine and 213g (1.65 mol of 1.3 eq) N, N-diisopropylethylamine, and 150mL dichloromethane. After the addition, the cold bath is removed, the temperature is returned to room temperature (25-30 ℃), and the reaction is stopped for 10 hours.
Post-treatment: to this, 200mL of water was added for extraction, and after stirring to dissolve the solution, the solution was allowed to stand for separation, and the aqueous layer was extracted with 200mL of dichloromethane. After standing and delamination, the organic layers were combined and washed with 200mL of water. After standing and layering, the organic layer was concentrated under reduced pressure to give 275g of (2-chloropyridin-4-yl) -piperidin-1-yl-methanone in a crude yield of 96.38% and a purity of 99.1%.
(2) Reduction reaction:
200g (1.11 mol,1.0 eq) of (2-chloropyridin-4-yl) -piperidin-1-yl-methanone crude product obtained above was added to a 1000mL four-necked flask, to which 600mL ethanol and 76.33g (0.56 mol,0.5 eq) of zinc chloride were added, and the solution was stirred. The temperature is controlled at 20-30 ℃, 37.83g (1.0 mol,0.9 eq) sodium borohydride powder is added in batches, the temperature is kept for 5 hours after the addition, and the reaction is stopped after sampling and monitoring that the consumption of (2-chloropyridin-4-yl) -piperidin-1-yl-methanone is less than 1 percent. 200mL of ice water is added into the reaction system for extraction and extinction at the temperature of 20-30 ℃, and 65g of 6N HCl is added into the reaction system for regulating the pH value to 6-7. Stirring for 0.5h, repeating the measurement of the pH value, and concentrating under reduced pressure to remove ethanol. Then 200ml of x 2 dichloromethane was added thereto for extraction, and the mixture was allowed to stand for separation. The organic layer was concentrated under reduced pressure to give 215g of crude 2-chloro-4- (1-piperidylmethyl) pyridine. The crude product is distilled under reduced pressure to obtain 204g of light yellow oily matter, namely the pure 2-chloro-4- (1-piperidylmethyl) pyridine. Yield 87.22% and purity 99.50%.
Therefore, when the preparation method is used for preparing the key intermediate 2-chloro-4- (1-piperidylmethyl) pyridine of lafutidine, the process steps are few, the yield of target products is high, and meanwhile, low-cost production raw materials are adopted, so that the production cost is greatly reduced, and the difficult problem in the prior art is solved.
The above description is only of the preferred embodiments of the present invention, and is not intended to limit the invention, but any modifications, equivalent substitutions, improvements, etc. within the design concept of the present invention should be included in the scope of the present invention.
Claims (10)
1. A process for preparing a key intermediate of lafutidine, characterized in that: the method comprises the following steps:
(1) Acylation: 2-chloroisonicotinic acid is taken as a starting material, and acyl chloride is prepared through acylation;
(2) Reaction with piperidine: reacting acyl chloride with piperidine to obtain (2-chloropyridin-4-yl) -piperidin-1-yl-methanone;
(3) Reduction reaction: reduction of (2-chloropyridin-4-yl) -piperidin-1-yl-methanone gives lafutidine key intermediate 2-chloro-4- (1-piperidylmethyl) pyridine.
2. A process for preparing a key intermediate of lafutidine according to claim 1, characterized in that: in the step (1), thionyl chloride is added to carry out acylation.
3. A process for preparing a key intermediate of lafutidine according to claim 1, characterized in that: in the step (1), when the consumption of the 2-chloroisonicotinic acid is detected to be less than 1%, the reaction is finished, then the piperidine is directly added into a reaction system without post-treatment, and the reaction in the step (2) is carried out.
4. A process for preparing a key intermediate of lafutidine according to claim 1, characterized in that: in the step (2), piperidine is firstly dissolved in an organic solvent to prepare a mixed solution, and then the mixed solution is added into a reaction system to react.
5. A process for preparing a key intermediate of lafutidine according to claim 1, characterized in that: after the step (2) is completed, post-processing operation is needed: adding water into the reaction system for extraction, adding an organic solvent for extraction, standing for extraction, taking an organic layer, adding water into the organic layer for washing, and concentrating the organic layer under reduced pressure to obtain (2-chloropyridin-4-yl) -piperidin-1-yl-methanone.
6. A process for preparing a key intermediate of lafutidine according to claim 1, characterized in that: in step (3), the reduction is performed with sodium borohydride.
7. A process for preparing a key intermediate of lafutidine according to claim 6, characterized in that: the sodium borohydride is added in portions.
8. A process for preparing a key intermediate of lafutidine according to claim 1, characterized in that: in the step (3), when the consumption of (2-chloropyridin-4-yl) -piperidin-1-yl-methanone is less than 1%, the reaction is stopped and the post-treatment is performed: adding water into the reaction system for extraction, adding HCl to adjust the pH value to 6-7, then concentrating under reduced pressure, adding an organic solvent for extraction, concentrating under reduced pressure and distilling under reduced pressure the extracted organic layer to obtain the target product 2-chloro-4- (1-piperidylmethyl) pyridine.
9. A process for preparing a key intermediate of lafutidine according to claim 1, characterized in that: in the preparation process, the molar ratio of the 2-chloroisonicotinic acid, the thionyl chloride, the piperidine and the sodium borohydride is 1:1-1.5:1-1.5:0.8-1.0.
10. A process for preparing a key intermediate of lafutidine according to claim 1, characterized in that: the preparation process is carried out in an organic system, wherein the organic solvent comprises one or a mixture of several of toluene, xylene, methylene dichloride, methanol, ethanol and N, N-dimethylformamide.
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