CN1613849A - Preparation of 2-Cl-5-F-nicotinate and nicotonic acid - Google Patents
Preparation of 2-Cl-5-F-nicotinate and nicotonic acid Download PDFInfo
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- CN1613849A CN1613849A CN 200310108336 CN200310108336A CN1613849A CN 1613849 A CN1613849 A CN 1613849A CN 200310108336 CN200310108336 CN 200310108336 CN 200310108336 A CN200310108336 A CN 200310108336A CN 1613849 A CN1613849 A CN 1613849A
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Abstract
Production of 2-chlorine-5-fluorine-nicotinate and acid is carried out by 2-chlorine-5-fluorine-nicotinate and related carboxylic acid selective dechlorinating, and 2-chlorine-5-fluorine-nicotinate hydrolyzing 2-chlorine-5-fluorine-niacin under the exist of alkaline substances. It can be used for 2-chlorine-5-fluorine-nicotinate and 2-chlorine-5-fluorine-niacin medicine intermediate.
Description
Technical field:
The present invention relates to have the preparation method of chlorine, fluorin radical nicotinate and nicotinic acid class pharmaceutical intermediate, particularly the preparation method of 2-chloro-5-fluoro-nicotinate and acid.
Background technology:
2-chloro-5-fluoro-nicotinate and 2-chloro-5-fluoro-nicotinic acid are the pharmaceutical intermediates of outbalance, but do not have effective synthetic method so far and prepare this product, once two kinds of preparation methods had been reported in the document, a kind of method is with 2,6-two chloro-5-fluoro-Nikithans at first react with thiomethyl alcohol, thereafter be that catalyst hydrogenation is taken off the first sulfydryl and obtained 2-chloro-5-fluoro-Nikithan with the Raney's nickel, hydrolysis obtains 2-chloro-5-fluoro-nicotinic acid (J.Med.Chem.1993.2678-2688) again; Another kind method is from 2-hydroxyl-nicotinic acid, nitrated chloro again gets 2-chloro-5-nitro-nicotinic acid earlier, it obtains 2-chloro-5-amino-nicotinic acid by iron powder reducing, and 2-chloro-5-amino-nicotinic acid obtains 2-chloro-5-fluoro-nicotinic acid (EP0634413A1) after the heating of gained NITRODIAZONIUM FLUOROBORATE after the diazotization in fluoroboric acid.
Document synthetic route 1:
Document synthetic route 2:
In document synthetic route 1, the one, must replace 2 with the thiomethyl alcohol of foreign odor, 6-two chloro-5-fluoro-Nikithans, take off the first sulfydryl with Raney's nickel for the catalyst hydrogenation selectivity simultaneously, yield has only about 30%, and the model of this reaction pair Raney's nickel is had relatively high expectations, and can not get product with general Raney's nickel; And document synthetic route 2 synthesis techniques are long, and last NITRODIAZONIUM FLUOROBORATE heating fluoro-reaction yield is crossed low and not easy to operate.
Summary of the invention:
The technical issues that need to address of the present invention are: the thiomethyl alcohol of avoiding using foreign odor in the preparation of 2-chloro-5-fluoro-nicotinate.Shorten the route of existing synthesis technique, improve yield, reduce cost.The method of a kind of 2-of preparation chloro-5-fluoro-nicotinate and 2-chloro-5-fluoro-nicotinic acid is provided.
Technical scheme of the present invention:
2-chloro-5-fluoro-nicotinate of the present invention and sour synthesis technique are as follows:
The present invention sloughs 2 by selectivity, 6-two chloro-5-fluoro-nicotinates and 2, and the method for 6 chlorine atom obtains its corresponding 2-chloro-5-fluoro-nicotinate and 2-chloro-5-fluoro-nicotinic acid in the 6-two chloro-5-fluoro-nicotinic acid.2-chloro-5-fluoro-nicotinic acid also can obtain by the hydrolysis of 2-chloro-5-fluoro-nicotinate.
In the above-mentioned technology, R is H, C
1～C
6Alkyl.We adopt the method for direct catalytic hydrogenation to 2,6-two chloro-5-fluoro-nicotinates and sour selectivity dechlorination.Catalyzer adopts lindlar catalyzer, Raney's nickel, palladium carbon etc., and consumption is 1～10% (W/W) of reaction substrate; Reaction solvent is methyl alcohol, ethanol, ethyl acetate, tetrahydrofuran (THF) etc.; And add the auxiliary agent of alkaline matter as the hydrogenation dechlorination, as triethylamine, Trimethylamine 99 etc.; Reaction pressure is normal pressure to 5 normal atmosphere; Temperature of reaction is 20～50 ℃.
Be hydrolyzed to 2-chloro-5-fluoro-nicotinic acid by 2-chloro-5-fluoro-nicotinate in the technology, this step reaction adopts alkaline matter as lithium hydroxide, sodium hydroxide, potassium hydroxide etc.; Temperature of reaction is a room temperature condition.
Beneficial effect of the present invention:
Reaction process of the present invention is selected rationally; it has adopted and has been easy to get, the raw material-2 of energy large-scale production; 6-two chloro-5-fluoro-nicotinates are (by 2; 6-two chloro-5-fluoro-3-cyanopyridines make; Japan special permission is open: 57-72981) and 2, the chlorine atom that the direct selectivity of 6-two chloro-5-fluoro-nicotinic acid is sloughed obtains corresponding 2-chloro-5-fluoro-nicotinic acid resin and 2-chloro-5-fluoro-nicotinic acid, and it has not only shortened the synthesis technique in the document; improved the synthetic yield, and can produce on a large scale.
Embodiment:
Embodiment 1
The first step: 2-chloro-5-fluoro-Nikithan synthetic
2, (50g, (32g, 0.32mol) and Lindlar catalyzer (2.5g), hydrogenation is 12 hours under 3 normal atmosphere, room temperature to add triethylamine in ethyl acetate solution 0.21mol) (1.2L) for 6-two chloro-5-fluoro-Nikithans.Remove by filter catalyzer, reaction solution concentrates the back column chromatography, obtains 2-chloro-5-fluoro-Nikithan (24.1g, 0.12mol, the productive rate: 55%) of colorless oil.
1H?NMR(400MHz，CDCl
3)：δ8.36(d，J＝2.8Hz，1H)，7.88(dd，J＝8.0?&?2.8Hz，1H)，4.40(q，J＝7.2Hz，2H)，1.39(t，J＝7.2Hz，2H)；
13C?NMR(400MHz，CDCl
3)：δ164.5(C)，160.5(C)，158.0(C)，146.0(d，J＝10.8Hz，C)，141.3(d，J＝99.6Hz，CH)，146.0(d，J＝10.8Hz，C)，129.2(d，J＝13.6Hz，C)，128.5(d，J＝85.4Hz，CH)，63.9(d，J＝48.0Hz，CH
2)，15.4(CH
3)；Ms(M
++1204206)。
Second step: 2-chloro-5-fluoro-nicotinic acid synthetic
2-chloro-5-fluoro-Nikithan (120g 0.59mol) is dissolved in 3: 1 methyl alcohol and water mixed solution (1.2L), under room temperature, add lithium hydroxide (contain a crystal water, 38.2g, 0.91mol).After the stirring at room one hour, be neutralized to PH=5-6, concentrate then and remove methyl alcohol with concentrated hydrochloric acid.Add frozen water (1L) under the residuum vigorous stirring, a large amount of white precipitates are separated out, and filter, and obtain most products (92.2g) after the oven dry; Water layer ethyl acetate extraction 3 times, the combined ethyl acetate extraction liquid concentrates the product (5.8g) that obtains remainder behind washing, the anhydrous sodium sulfate drying.Obtain product 98g (0.56mol) productive rate altogether: 95%.
1HNMR(400MHz，DMSO-d
6)：δ8.60(d，J＝2.8Hz，1H)，8.18(dd，J＝8.4?&?2.8Hz，1H)；Ms(M
++1176178)。
Embodiment 2
Synthesizing of 2-ammonia-5-fluoro-Nikithan
2, (50g, (32g, 0.32mol) and 5%Pd-C catalyzer (1.0g), hydrogenation is 12 hours under atmospheric pressure at room to add triethylamine in ethyl acetate solution 0.21mol) (1.2L) for 6-two chloro-5-fluoro-Nikithans.Remove by filter catalyzer, reaction solution concentrates the back column chromatography, obtains buttery 2-chloro-5-fluoro-Nikithan (18.4g, 0.09mol, productive rate: 43%).
Embodiment 3
Synthesizing of 2-chloro-5-fluoro-Nikithan
2, (50g, (32g, 0.32mol) and 5% Raney's nickel (1.0g), in normal pressure, temperature is 40 ℃ of following hydrogenations 12 hours to 6-two chloro-5-fluoro-Nikithans to add triethylamine in ethyl acetate solution 0.21mol) (1.2L).Remove by filter catalyzer, reaction solution concentrates the back column chromatography, obtains buttery 2-chloro-5-fluoro-Nikithan (18.4g, 0.09mol, productive rate: 25%).
Embodiment 4
Synthesizing of 2-chloro-5-fluoro-nicotinic acid methyl ester
2,6-two chloro-5-fluoro-nicotinic acid methyl esters (50g, add in ethyl acetate solution 0.21mol) (1.2L) triethylamine (33.3g, 0.33mol) and 5% Raney's nickel (1.0g), in 3 normal atmosphere, temperature 40 ℃ of following hydrogenations 12 hours.Remove by filter catalyzer, reaction solution concentrates the back column chromatography, obtains buttery 2-chloro-5-fluoro-nicotinic acid methyl ester (21.2g, 0.11mol, productive rate: 50%).
1H?NMR(400MHz，CDCl
3)：δ8.36(d，J＝2.8Hz，1H)，7.88(dd，J＝8.0?&?2.8Hz，1H)，3.94(s，3H)，Ms(M
++1190192)。
Embodiment 5
Synthesizing of 2-chloro-5-fluoro-isopropyl nicotinate
2, (50g, (30.3g, 0.30mol) and Lindlar catalyzer (2.5g), hydrogenation is 12 hours under 3 normal atmosphere, room temperature to add triethylamine in ethyl acetate solution 0.20mol) (1.2L) for 6-two chloro-5-fluoro-isopropyl nicotinates.Remove by filter catalyzer, reaction solution concentrates the back column chromatography, obtains buttery 2-chloro-5-fluoro-nicotinic acid methyl ester (24.3g, 0.112mol, productive rate: 56%).
1H?NMR(400MHz，CDCl
3)：δ8.37(d，J＝2.8Hz，1H)，7.87(dd，J＝8.0?&?2.8Hz，1H)，5.28(m，J＝6.0Hz，1H)，1.40(d，J＝6.0Hz，6H).Ms(M
++1，218，220).
Embodiment 6
Synthesizing of 2-chloro-5-fluoro-nicotinic acid
2,6-two chloro-5-fluoro-nicotinic acid (10g, add in ethanolic soln 0.048mol) (150mL) triethylamine (6g, 0.059mol) and Lindlar catalyzer (0.5g), under 3 normal atmosphere, normal temperature hydrogenation 12 hours.Remove by filter catalyzer, reaction solution concentrates the back column chromatography, obtains 2-chloro-5-fluoro-nicotinic acid (2.1g, 0.012mol, productive rate: 25%).
Claims (8)
1, the preparation method of 2-chloro-5-fluoro-nicotinate is characterized in that, sloughs 2 by the method selectivity of direct catalytic hydrogenation, and 6 chlorine atom obtains its corresponding 2-chloro-5-fluoro-nicotinate in the 6-two chloro-5-fluoro-nicotinates.
2, the preparation method of 2-chloro-5-fluoro-nicotinate according to claim 1 is characterized in that the reaction formula of above-mentioned reaction is:
In the above-mentioned technology, R is C
1～C
6Alkyl, catalyzer adopts a kind of in lindlar catalyzer, Raney's nickel, the palladium carbon, consumption is 1～10% (W/W) of reaction substrate, reaction solvent is methyl alcohol, ethanol, ethyl acetate, a kind of in the tetrahydrofuran (THF), and add the auxiliary agent of alkaline matter as the hydrogenation dechlorination, as triethylamine, Trimethylamine 99.
3, the preparation method of 2-chloro-5-fluoro-nicotinate according to claim 1 and 2 is characterized in that, reaction pressure is normal pressure to 5 normal atmosphere; Temperature of reaction is 20～50 ℃.
4, the preparation method of 2-chloro-5-fluoro-nicotinic acid is characterized in that, sloughs 2 by the method selectivity of direct catalytic hydrogenation, and 6 chlorine atom obtains its corresponding 2-chloro-5-fluoro-nicotinic acid in the 6-two chloro-5-fluoro-nicotinic acid.
5,, the preparation method of 2-chloro-5-fluoro-nicotinic acid according to claim 4, it is characterized in that the reaction formula of above-mentioned reaction is:
In the above-mentioned technology, catalyzer adopts a kind of in lindlar catalyzer, Raney's nickel, the palladium carbon, consumption is 1～10% (W/W) of reaction substrate, reaction solvent is methyl alcohol, ethanol, ethyl acetate, a kind of in the tetrahydrofuran (THF), and add the auxiliary agent of alkaline matter as the hydrogenation dechlorination, as triethylamine, Trimethylamine 99.
6, according to the preparation method of claim 4 or 5 described 2-chloro-5-fluoro-nicotinic acid, it is characterized in that reaction pressure is normal pressure to 5 normal atmosphere; Temperature of reaction is 20～50 ℃.
7, the preparation method of 2-chloro-5-fluoro-nicotinic acid is characterized in that, at first preparation power 1 described 2-chloro-5-fluoro-nicotinate, and 2-chloro-5-fluoro-nicotinate is hydrolyzed to 2-chloro-5-fluoro-nicotinic acid in the presence of alkaline matter.
8, the preparation method of 2-chloro-5-fluoro-nicotinic acid according to claim 7 is characterized in that, this goes on foot anti-alkaline matter and adopts a kind of in lithium hydroxide, sodium hydroxide, the potassium hydroxide, and temperature of reaction is a room temperature condition.
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| US8859569B2 (en) | 2011-09-02 | 2014-10-14 | Bayer Pharma Aktiengesellschaft | Substituted annellated pyrimidines and use thereof |
| DE102012200351A1 (en) | 2012-01-11 | 2013-07-11 | Bayer Pharma Aktiengesellschaft | New substituted annellated pyrimidine compounds are guanylate cyclase stimulators useful to treat and/or prevent heart failure, hypertension, ischemia, vascular disease, renal failure, thromboembolic disorders and fibrotic diseases |
| US9505786B2 (en) | 2012-01-11 | 2016-11-29 | Bayer Pharma Aktiengesellschaft | Substituted annulated triazines and use thereof |
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| DE102012200354A1 (en) | 2012-01-11 | 2013-07-11 | Bayer Intellectual Property Gmbh | New heteroaryl-substituted pyrazolopyridine compounds are soluble guanylate cyclase stimulators, useful to treat e.g. heart disease, angina pectoris, hypertension, pulmonary hypertension, ischemia, vascular disease or renal insufficiency |
| US9498480B2 (en) | 2012-03-06 | 2016-11-22 | Bayer Intellectual Property Gmbh | Substituted azabicycles and use thereof |
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| US10662188B2 (en) | 2013-02-21 | 2020-05-26 | Adverio Pharma Gmbh | Forms of methyl {4,6-diamino-2-[1 (2-fluorobenzyl)-1H-pyrazolo[3-4-b]pyridino-3-yl]pyrimidino-5-yl} methyl carbamate |
| US11203593B2 (en) | 2013-02-21 | 2021-12-21 | Adverio Pharma Gmbh | Forms of methyl {4,6-diamino-2-[1(2-fluorobenzyl)-1H-pyrazolo[3-4-b]pyridino-3-yl]pyrimidino-5-yl}methyl carbamate |
| US9266871B2 (en) | 2013-03-01 | 2016-02-23 | Bayer Pharma Aktiengesellschaft | Trifluoromethyl-substituted fused pyrimidines and their use |
| US9605008B2 (en) | 2013-07-10 | 2017-03-28 | Bayer Pharma Aktiengesellschaft | Benzyl-1H-pyrazolo[3,4-b]pyridines and use thereof |
| WO2017121700A1 (en) | 2016-01-15 | 2017-07-20 | Bayer Pharma Aktiengesellschaft | 1,3-disubstituted 1h-pyrazolo[3,4-b]pyridine derivatives and use thereof as stimulators of soluble guanylate cyclase |
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| CN100355732C (en) | 2007-12-19 |
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