CN101029023A - Production of picolyl ether and its salt - Google Patents
Production of picolyl ether and its salt Download PDFInfo
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- CN101029023A CN101029023A CN 200710026678 CN200710026678A CN101029023A CN 101029023 A CN101029023 A CN 101029023A CN 200710026678 CN200710026678 CN 200710026678 CN 200710026678 A CN200710026678 A CN 200710026678A CN 101029023 A CN101029023 A CN 101029023A
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Abstract
A process for preparing the pyridine formamidine and its salt with high output rate and purity includes such steps as preparing hydroxyamido oxime as intermediate, and hydrogenating and reducing in the liquid mixture of acetic acid and acetic anhydride.
Description
Technical field:
The present invention relates to a kind of preparation of medicine intermediate, refer in particular to the preparation method who contains amidino compounds and salt thereof.
Background technology:
The preparation approach of the amidine of having reported has a lot, is listed below:
(1) relates to halo itrile group pyridine and ammonium salt direct addition in the presence of highly basic among U.S. Pat 6696451, the Chinese patent ZL99807495.0.The deficiency of this method is: need use extremely inflammable, severe corrosive, the chemical trimethyl aluminium big to environmental hazard, and yield (39.1%) on the low side.
(2) P.C.Srivastava, J.Med.Chem.27, the method that relates in (1984) 266 is with the pressurization of liquefied ammonia form, and ammonia is directly added in the aryl nitrile.The deficiency of this method is: long reaction time (16h), and with studies show that the replacement nitrile carries out, even to depress transformation efficiency also limited and cause the amidine yield corresponding lower thus adding.
(3) Ber.18 (1885) 2845) in relate to through after the Pinner reaction again with the imino carboxylic acid ester aminolysis, the deficiency of this method is: two-step reaction, need to use a large amount of hydrogenchloride, the a large amount of salt by product of final generation, sometimes cause the later separation difficulty, and there is long reaction time equally in this reaction, can only obtain medium yield thereby transformation efficiency is on the low side.
(4) at R.C.Schnur, J.Org.Chem.44, (1979) 3726; H.Rappoport, J.Org.Chem.46, (1981) 2455; M.Ohno relates among the Tetrahedeonlett. (1979) 2517 to use mercaptan to prepare amidine as assistant agent or add hydrogen sulfide in nitrile and obtains thiocarboxamide, then sulfur alkylation and ammonia is separated.The deficiency of this method is: above-mentioned arts demand is used compound extremely smelly and that toxicity is high, and strong carcinogens such as methyl iodide or methyl-sulfate is generally used in alkylation.
Summary of the invention:
The objective of the invention is to overcome above carbonamidine preparation method's deficiency, provide a kind of easy and simple to handle, raw material is easy to get, and the reaction times is short, the preparation method of the carbonamidine that yield height and product purity are high.
One, the method for preparing The compounds of this invention can be described with following reaction formula:
xCH3COOH
Wherein, R
1, R
2Independently represent F or Cl or Br separately.
At normal temperatures, make the above-mentioned N of containing fragrance nitrile and oxyamine be reacted into corresponding hydroxyl amidoxime under the condition that alkali exists, the back is hydrogenated to the method for carbonamidine pyridine under Pd/C catalysis with acetic acid, aceticanhydride mixture.
Two, the present invention realizes by following steps:
(1) add above-mentioned halogeno-cyanogen yl pyridines in reactor: oxammonium hydrochloride: bases compound mol ratio is 1: 1: 1～1: 4: 4 a compound, and the mixed solvent of water and methyl alcohol or ethanol or Virahol, stirring at normal temperature, suction filtration vacuum-drying obtain corresponding hydroxyl amidoxime
(2) add acetic acid in the hydrogenation still: the aceticanhydride volume ratio is (25-40): 1 mixed solvent, again hydroxyl oxime pyridine is dropped in the reactor, and stir and form settled solution, drop into Pd/C to the reactor back end hydrogenation by (5-30) gPd/C:1mol hydroxyl oxime pyridine.
(3) suction filtration is removed Pd/C, and acetic acid is removed in underpressure distillation, uses the acetone crystallization when closely dried, and suction filtration vacuum-drying obtains corresponding product carbonamidine PAA salt.
The present invention adopts above-mentioned technology, the midbody product hydroxyl amidoxime for preparing high purity (＞98%) that can be very easy at normal temperatures, by hydro-reduction in the mixed solution of acetic acid and aceticanhydride, can obtain the amidine of high yield, high purity (＞98%), compare with background technology, advantages such as the present invention has the yield height, and technology is simple, and toxic side effect is little.
Embodiment:
Embodiment 1
Preparation 3, the method for 5-two fluoro-2-carbonamidine PAA salt
CH3COOH
Specifically may further comprise the steps:
(1): in reactor, add 200ml water and 30ml methyl alcohol, 10g (0.07mol) 3-5-two fluoro-2-cyanopyridines.
(2): in reactor, add 20g (0.28mol) oxammonium hydrochloride and 15g (0.14mol) yellow soda ash.
(3): stir 2h, suction filtration, 60 ℃ of vacuum-dryings obtain 12g 3,5-two fluoro-2-hydroxyl oxime pyridines, HPLC purity is 99%.
(4): in the hydrogenation still, add 250ml acetic acid, the 10ml aceticanhydride, 10g (0.063mol) above-mentioned 3,5-two fluoro-2-hydroxyl oxime pyridines stir 10min, add 1gPd/C in reactor, hydrogenation stops behind the 2h.
(5): cross filtering Pd/C, acetic acid is removed in 60 ℃ of underpressure distillation, and with the crystallization of 200ml acetone, suction filtration obtains 3 when closely dried, 5-two fluoro-2-carbonamidine PAA salt, and 60 ℃ of vacuum-dryings obtain 12g 3,5-two fluoro-2-carbonamidine PAA salt, HPLC purity＞99%.
Embodiment 2
The method for preparing 3-bromo-5-fluoro-2-carbonamidine PAA salt
CH3COOH
Specifically may further comprise the steps:
(1): in reactor, add 1500ml water and 140ml ethanol, 50g (0.25mol) 3-bromo-5-fluoro-2-cyanopyridine.
(2): in reactor, add 24g (0.35mol) oxammonium hydrochloride and 16.8g (0.42mol) sodium hydroxide.
(3): stir 2h, suction filtration, 60 ℃ of vacuum-dryings obtain 67g (0.306mol) 3-bromo-5-fluoro-2-hydroxyl oxime pyridine, and HPLC purity is 99.3%.
(4): in the hydrogenation still, add 600ml acetic acid, the 20ml aceticanhydride, the 3-bromo-5-fluoro-2-hydroxyl oxime pyridine that 20g (0.09mol) is above-mentioned stirs 10min, adds 2gPd/C in reactor, and hydrogenation stops behind the 2h.
(5): cross filtering Pd/C, acetic acid is removed in 60 ℃ of underpressure distillation, uses the crystallization of 1100ml acetone when closely dried, suction filtration obtains 3-bromo-5-fluoro-2-carbonamidine PAA salt, 60 ℃ of vacuum-dryings obtain 23.8g 3-bromo-5-fluoro-2-carbonamidine PAA salt, HPLC purity＞98%.
Embodiment 3
The method for preparing 3-chloro-5-fluoro-2-carbonamidine PAA salt
CH3COOH
Specifically may further comprise the steps:
(1): in reactor, add 600ml water and 60ml methyl alcohol, 30g (0.19mol) 3-chloro-5-fluoro-2-cyanopyridine.
(2): in reactor, add 23.63g (0.34mol) oxammonium hydrochloride and 43.2g (0.4mol) yellow soda ash.
(3): stir 2h, suction filtration, 60 ℃ of vacuum-dryings obtain 33.5g (0.192mol) 3-chloro-5-fluoro-2-hydroxyl oxime pyridine, and HPLC purity is 99%.
(4): in the hydrogenation still, add 600ml acetic acid, the 25ml aceticanhydride, the 3-chloro-5-fluoro-2-hydroxyl oxime pyridine that 30g (0.172mol) is above-mentioned stirs 10min, adds 2.5gPd/C in reactor, and hydrogenation stops behind the 2h.
(5): cross filtering Pd/C, acetic acid is removed in 60 ℃ of underpressure distillation, and with the crystallization of 500ml acetone, suction filtration obtains 3-chloro-5-fluoro-2-carbonamidine PAA salt when closely dried, and 60 ℃ of vacuum-dryings obtain 36g 3-chloro-5-fluoro-2-carbonamidine PAA salt, HPLC purity＞99%.
Embodiment 4
Preparation 3, the method for 5-two chloro-2-carbonamidine PAA salt
CH3COOH
Specifically may further comprise the steps:
(1): in reactor, add 2000ml water and 300ml methyl alcohol, 100g (0.58mol) 3,5-two chloro-2-cyanopyridines.
(2): in reactor, add 80.6g (1.16mol) oxammonium hydrochloride and 51g (1.28mol) sodium hydroxide.
(3): stir 2h, suction filtration, 60 ℃ of vacuum-dryings obtain 115g 3,5-two chloro-2-hydroxyl oxime pyridines, HPLC purity is 98.7%.
(4): in the hydrogenation still, add 2300ml acetic acid, the 85ml aceticanhydride, 100g (0.52mol) above-mentioned 3,5-two fluoro-2-hydroxyl oxime pyridines stir 10min, add 6gPd/C in reactor, hydrogenation stops behind the 2h.
(5): cross filtering Pd/C, acetic acid is removed in 60 ℃ of underpressure distillation, and with the crystallization of 1000ml acetone, suction filtration obtains 3 when closely dried, 5-two chloro-2-carbonamidine PAA salt, and 60 ℃ of vacuum-dryings obtain 119g 3,5-two chloro-2-carbonamidine PAA salt, HPLC purity＞98%.
Claims (1)
1, the preparation method of a kind of picolyl ether and salt thereof is characterized in that:
One, it can be represented with following reaction formula:
Wherein, R
1, R
2Independently represent F or Cl or Br separately.
At normal temperatures, make the above-mentioned N of containing fragrance nitrile and oxyamine be reacted into corresponding hydroxyl amidoxime under the condition that alkali exists, the back is hydrogenated to the method for carbonamidine pyridine under Pd/C catalysis with acetic acid, aceticanhydride mixed solvent.
Two, it is to be realized by following steps:
(1) add above-mentioned halogeno-cyanogen yl pyridines in reactor: oxammonium hydrochloride: bases compound mol ratio is 1: 1: 1～1: 4: 4 a compound, and the mixed solvent of water and methyl alcohol or ethanol or Virahol, stirring at normal temperature, suction filtration vacuum-drying obtain corresponding hydroxyl amidoxime
(2) add acetic acid in the hydrogenation still: the aceticanhydride volume ratio is (25～40): 1 mixed solvent, again hydroxyl oxime pyridine is dropped in the reactor, and stir and form settled solution, press (5～30) gPd/C: 1mol hydroxyl oxime pyridine drops into Pd/C to the reactor back end hydrogenation.
(3) suction filtration is removed Pd/C, and acetic acid is removed in underpressure distillation, uses the acetone crystallization when closely dried, and suction filtration vacuum-drying obtains corresponding product carbonamidine PAA salt.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2007100266787A CN100494178C (en) | 2007-02-02 | 2007-02-02 | Production of pyridil carbonamidine and its salt |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2007100266787A CN100494178C (en) | 2007-02-02 | 2007-02-02 | Production of pyridil carbonamidine and its salt |
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| CN101029023A true CN101029023A (en) | 2007-09-05 |
| CN100494178C CN100494178C (en) | 2009-06-03 |
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|---|---|---|---|
| CNB2007100266787A Active CN100494178C (en) | 2007-02-02 | 2007-02-02 | Production of pyridil carbonamidine and its salt |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115043757A (en) * | 2022-07-27 | 2022-09-13 | 南京桦冠生物技术有限公司 | Method for continuously preparing benzamidine hydrochloride |
-
2007
- 2007-02-02 CN CNB2007100266787A patent/CN100494178C/en active Active
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115043757A (en) * | 2022-07-27 | 2022-09-13 | 南京桦冠生物技术有限公司 | Method for continuously preparing benzamidine hydrochloride |
| CN115043757B (en) * | 2022-07-27 | 2023-08-08 | 南京桦冠生物技术有限公司 | Method for continuously preparing benzamidine hydrochloride |
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| CN100494178C (en) | 2009-06-03 |
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Address after: 443300 Binjiang Road, Yidu, Hubei, No. 38, No. Patentee after: YICHANG HEC CHANGJIANG PHARMACEUTICAL CO., LTD. Address before: 443300 Binjiang Road, Yidu, Hubei, No. 38, No. Patentee before: HEC Pharmaceutical Company |