CN105622444A - Preparation method for 1-benzyl-3-piperidone hydrochloride - Google Patents
Preparation method for 1-benzyl-3-piperidone hydrochloride Download PDFInfo
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- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
- C07C227/06—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid
- C07C227/08—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid by reaction of ammonia or amines with acids containing functional groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
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Abstract
The invention discloses a preparation method for N-benzyl glycine ethyl ester. The method comprises the following steps: dissolving benzylamine in an organic solvent I, then adding 2-halogenated ethyl acetate, alkali and quaternary ammonium salt, and performing reaction to obtain the N-benzyl glycine ethyl ester. The invention also discloses a preparation method for 1-benzyl-3-piperidone hydrochloride. The method comprises the following specific steps: (1) preparing an intermediate IV (N-benzyl glycine ethyl ester); (2) dissolving the intermediate IV in an organic solvent II, then adding 4-halogenated ethyl acetate and alkali, and performing reaction to obtain an intermediate III; (3) performing reaction between the intermediate III and the alkali, reversely regulating a pH value to 6-8, performing concentration under reduced pressure, extracting by using ethyl acetate, performing washing and drying, and then performing concentration under reduced pressure to obtain an intermediate II; (4) performing reaction on the intermediate II and acid, performing rotary evaporation concentration, and adding a crystal solvent for crystallization to obtain a product. The route synthesis steps are short, the process is novel, the intermediates are high in purity, the product yield is high, and the cost is low.
Description
Technical field
The present invention relates to organic synthesis field, particularly to the preparation method of a kind of 1-benzyl-3-piperidone hydrochloride.
Background technology
Halofuginone hydrobromide (Halofuginone, WR237645), have another name called bromine chlorine halofuginone hydrobromide, halogen quinoline ketone, Lu's husband's ketone, be the halo derivatives of a kind of quinazoline ketones alkaloid orixine (Febrifugine) separated from plant Radix Dichroae (Dichroafebrifuga). Halofuginone hydrobromide has strong insecticidal activity, and multiple Eimeria species is all had stronger inhibitory or killing effect, is now produced by Hirst company of Germany, trade name " speed is red " (). The chemical structural formula of halofuginone hydrobromide orixine is as follows:
1-benzyl-3-piperidone hydrochloride is a kind of important chemical intermediate, can as the starting material preparing hydrobromic acid antifebrile dichroanone, it is also possible to replace the synthesis of Buddhist nun (Ibrutinib) etc. for antimicrobial drug Q-35 (Balofloxacin) and leukemia stype Shandong. The chemical structural formula of 1-benzyl-3-piperidone hydrochloride is as follows:
Li Weidong et al. efficient, succinct preparation method of a kind of hydrobromic acid antifebrile dichroanone disclosed in Chinese patent CN101987843, the starting material of the method is 1-benzyl-3-piperidone hydrochloride, but the preparation method not disclosing this starting material in the patent.
The route of synthesis of current 1-benzyl-3-piperidone hydrochloride mainly has following three:
(1) Chinese Journal of Pharmaceuticals, 2004,35 (7): 385 documents are reported with gamma-butyrolacton for raw material, through benzylamine aminolysis, hydrochloric acid hydrolysis, esterification, obtaining 1-benzyl-3-piperidone hydrochloride with hydrolysis after bromoacetate condensation, cyclization, reaction equation is as follows:
This preparation method route is long, and total recovery is only 18.27%.
(2) Synlett, 2006, (7): 1440 documents are reported with 3-pyridone for raw material, it is 3-hydroxy piperidine through platinum dioxide catalytic hydrogenation, then N is Benzylation, and finally oxidation hydroxyl is that carbonyl obtains 1-benzyl-3-piperidones, and reaction equation is as follows:
The hydro-reduction step of this preparation method uses the noble metal catalyst of the high cost such as platinum dioxide, platinum carbon, and initiation material 3-pyridone and catalyst cause the high cost of this route.
(3) Chinese patent CN102351783 is with 3-pyridone for raw material, first passes through N benzyl chemical conversion quaternary ammonium salt, and then finally aoxidizing hydroxyl with sodium borohydride reduction pyridine ring is that carbonyl obtains 1-benzyl-3-piperidones, and reaction equation is as follows:
The hydro-reduction step of this preparation method is transformed to sodium borohydride, finally adopts Swern method oxidation hydroxyl to become ketone, and it is relatively costly that the initiation material 3-pyridone of this route and sodium borohydride are led, and oxidizing condition is harsh, and temperature is-70 DEG C.
Therefore a kind of low cost, easy method are needed badly for preparing 1-benzyl-3-piperidone hydrochloride.
Summary of the invention
Present invention aims to above technical problem, it is provided that a kind of synthetic route shortens, reaction reagent Material Cost is low, the preparation method of concise production process, high-purity 1-benzyl-3-piperidone hydrochloride.
Technical scheme is as follows:
The preparation method of a kind of N-n-benzylglycine ethyl ester, comprises the steps: to be dissolved in organic solvent I by benzylamine, is subsequently adding 2-halogenated acetic acids ethyl ester, alkali, quaternary ammonium salt, is obtained by reacting N-n-benzylglycine ethyl ester.
In technique scheme, described organic solvent I is selected from acetonitrile, dichloromethane, chloroform, carbon tetrachloride, oxolane, toluene or benzene; Described 2-halogenated acetic acids ethyl ester is 2-ethyl chloroacetate or 2-bromoethyl acetate; Described alkali is selected from triethylamine, diisopropylethylamine, pyridine, sodium carbonate or potassium carbonate; Described quaternary ammonium salt is selected from hydrogen sulfate TBuA, benzyltriethylammonium chloride or Dodecyl trimethyl ammonium chloride.
As preferably, described benzylamine, 2-halogenated acetic acids ethyl ester, alkali, quaternary ammonium salt mol ratio be 1:1��3:1��3:0.1��0.5.
A kind of preparation method of 1-benzyl-3-piperidone hydrochloride, reaction equation is:
Concretely comprise the following steps:
(1) intermediate compound IV (N-n-benzylglycine ethyl ester) is prepared according to preceding method;
(2) intermediate compound IV is dissolved in organic solvent II, is subsequently adding 4-halo ethyl n-butyrate., alkali, is obtained by reacting intermediate III;
(3) by described intermediate III and alkali reaction, regulating pH value after completion of the reaction is 6-8, concentrating under reduced pressure, and concentrated solution ethyl acetate is extracted, washing, dry, again concentrating under reduced pressure obtain intermediate II;
(4) by described intermediate II and acid reaction, after having reacted, rotation steaming obtains concentrated solution, adds recrystallisation solvent crystallization and obtain product in concentrated solution.
In technique scheme, in step 2, described organic solvent II is selected from chloroform, carbon tetrachloride, oxolane, toluene or benzene; Described 4-halo ethyl n-butyrate. is 4-chloro ethyl n-butyrate. or 4-bromobutyrate; Described alkali is selected from sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide or Lithium hydrate; As preferably, described intermediate compound IV, 4-halo ethyl n-butyrate., alkali mol ratio be 1:1��2:1��3.
In technique scheme, in step 3, described alkali is selected from sodium tert-butoxide, potassium tert-butoxide, Sodium ethylate, potassium ethoxide, Feldalat NM or Feldalat KM. As preferably, the mol ratio of described intermediate III and alkali is 1:1��3.
In technique scheme, in step 4, described acid is hydrochloric acid. As preferably, described recrystallisation solvent is selected from acetonitrile, ethyl acetate or isopropanol; Described intermediate II is 1:3��10 with sour mol ratio.
The invention has the beneficial effects as follows: the present invention is generate monoalkylated product N-n-benzylglycine ethyl ester when organic solvent and alkali under initiation material and 2-halogenated acetic acids ethyl ester condensation reaction, selection quaternary ammonium salt catalysis with benzylamine, dialkyl impurity is effectively controlled, and the N-n-benzylglycine ethyl ester purity obtained is high; Present invention also offers the N-n-benzylglycine ethyl ester and 4-halogenated acetic acids ethyl ester condensation that the inventive method are prepared, then cyclization is the piperidine ring replaced, the finally de-ester of hydrolysis, the method preparing 1-benzyl-3-piperidone hydrochloride, this is new synthetic route, this routine synthetic steps is short, new technology, intermediate purity is high, low cost of raw materials, and technological operation is simple, product yield is high, quality is good, it is easy to industrialized production.
Detailed description of the invention
Embodiment 1 prepares 1-benzyl-3-piperidone hydrochloride
Operation in accordance with the following steps:
(1) preparation of intermediate compound IV
The there-necked flask of 1000mL is sequentially added into benzylamine 43g (0.4mol), acetonitrile 250mL, hydrogen sulfate TBuA 13.3g (0.04mol), stir under triethylamine 40.4g (0.4mol) room temperature, the solution of dropping 2-ethyl chloroacetate 49g (0.4mol) and acetonitrile 150mL, drip to be incubated after finishing and react 4h at 25-28 DEG C, HPLC detection reaction is finished, reactant liquor stands 1.5h at being cooled to 0-5 DEG C, filter, filtrate reduced in volume obtains light brown grease (i.e. intermediate compound IV) 80.5g (yield 104%), HPLC detects purity 98.2%, direct plunge into next step reaction.
(2) preparation of intermediate III
The there-necked flask of 1000mL adds intermediate compound IV 80.5g (0.4mol) prepared by previous step, add oxolane 500mL to dissolve, add 4-bromobutyrate 78g (0.4mol), add sodium carbonate 42.4g (0.4mol), heated and stirred refluxes, being incubated after reacting 24h, HPLC detection reaction substantially completely at 66-68 DEG C, reactant liquor is cooled to room temperature, filter, filtrate is intermediate III, direct plunges into next step reaction, and HPLC detects purity 95.2%.
(3) preparation of intermediate II
The there-necked flask of 1000mL adds the intermediate III tetrahydrofuran solution prepared of previous step, is subsequently adding sodium tert-butoxide 38.5g (0.4mol), heat to 66-68 DEG C anti-under reflux 5h. After HPLC detection reacts completely, reactant liquor cools down, and adding acetic acid 39g adjustment pH value is 7, reaction system proceeds to concentrating under reduced pressure in flask, adds ethyl acetate 500mL, tap water 200mL in concentrate, stirring layering, proceed in separatory funnel, organic layer washed with water, then dry, filter, filtrate concentrate grease is intermediate II (N-benzyl-3-oxo-piperidine-4-Ethyl formate) 90.8g, concentrate direct plunges into next step reaction, and the HPLC of concentrate detects purity 92.6%.
(4) preparation of target compound I
In the there-necked flask of 1000mL, add above-mentioned prepared intermediate II 90.8g (0.35mol), be subsequently adding concentrated hydrochloric acid 87.5mL (1.05molHCl) that concentration is 12mol/L, be heated to reflux 4h, t=86 DEG C. HPLC detection reacts completely, reaction system is cooled to room temperature, reactant liquor rotation being steamed (70 DEG C) concentration anhydrate point and hydrogen chloride, concentrated solution is separately added into 150mL acetonitrile, addition crystal seed, stirring and crystallizing 2-4h under room temperature, filter, collect off-white color filter cake, vacuum drying 4h at 80 DEG C, weigh compound I (1-benzyl-3-piperidone hydrochloride) monohydrate 63.5g (yield 65.1%), HPLC detect purity 99.4%.
Embodiment 2 prepares 1-benzyl-3-piperidone hydrochloride
Operation in accordance with the following steps:
(1) preparation of intermediate compound IV
The there-necked flask of 1000mL is sequentially added into benzylamine 43g (0.4mol), dichloromethane 250mL, benzyltriethylammonium chloride 45.6g (0.2mol), stir under diisopropylethylamine 154.8g (1.2mol) room temperature, the solution of dropping 2-bromoacetate 217.3g (1.2mol) and dichloromethane 150mL, drip to be incubated after finishing and react 4h at 25-28 DEG C, HPLC detection reaction is finished, reactant liquor stands 1.5h at being cooled to 0-5 DEG C, filter, filtrate reduced in volume obtains light brown grease (i.e. intermediate compound IV) 75.5g (yield 97.7%), HPLC detects purity 98.4%, direct plunge into next step reaction.
(2) preparation of intermediate III
The there-necked flask of 1000mL adds intermediate compound IV 75.5g (0.39mol) prepared by previous step, add chloroform 500mL to dissolve, add 4-chloro ethyl n-butyrate. 152g (0.78mol), add potassium carbonate 161.5g (1.17mol), heated and stirred refluxes, it is incubated and reacts 24h at 66-68 DEG C, after HPLC detection reaction substantially completely, reactant liquor is cooled to room temperature, filter, filtrate is intermediate III, and filtrate direct plunges into next step reaction, and HPLC detects purity 95.7%.
(3) preparation of intermediate II
The there-necked flask of 1000mL adds the intermediate III prepared of previous step, is subsequently adding potassium tert-butoxide 131g (1.17mol), heat to 66-68 DEG C anti-under reflux 5h. After HPLC detection reacts completely, reactant liquor cools down, adding acetic acid 39g adjustment pH value is 7, reaction system proceeds to concentrating under reduced pressure in flask, concentrate adds ethyl acetate 500mL, tap water 200mL, stirring layering, proceed in separatory funnel, organic layer washed with water, then dry, filter, filtrate concentrate brown oil is intermediate II (N-benzyl-3-oxo-piperidine-4-Ethyl formate) 90.8g, concentrate direct plunges into next step reaction, and the HPLC of concentrate detects purity 93.2%.
(4) preparation of target compound I
In the there-necked flask of 1000mL, add the intermediate II 90.8g (0.35mol) that previous step prepares, be subsequently adding concentrated hydrochloric acid 292mL (3.5molHCl) that concentration is 12mol/L, be heated to reflux 5h, t=86-88 DEG C. HPLC detection reacts completely, reaction system is cooled to room temperature, reactant liquor rotation being steamed (70 DEG C) concentration anhydrate point and hydrogen chloride, concentrated solution is separately added into 150mL isopropanol, addition crystal seed, stirring and crystallizing 2-4h under room temperature, filter, collect off-white color filter cake, vacuum drying 4h at 80 DEG C, weigh compound I (1-benzyl-3-piperidone hydrochloride) monohydrate 58.8g (yield 60.3%), HPLC detect purity 99.6%.
Embodiment 3 prepares 1-benzyl-3-piperidone hydrochloride
Operation in accordance with the following steps:
(1) preparation of intermediate compound IV
The there-necked flask of 1000mL is sequentially added into benzylamine 43g (0.4mol), toluene 250mL, Dodecyl trimethyl ammonium chloride 15g (0.057mol), stir under pyridine 39.5g (0.5mol) room temperature, the solution of dropping 2-ethyl chloroacetate 55g (0.45mol) and toluene 150mL, drip to be incubated after finishing and react 4h at 25-28 DEG C, HPLC detection reaction is finished, reactant liquor stands 1.5h at being cooled to 0-5 DEG C, filter, filtrate reduced in volume obtains light brown grease (i.e. intermediate compound IV) 81.0g (yield 105%), HPLC detects purity 96.2%, direct plunge into next step reaction.
(2) preparation of intermediate III
The there-necked flask of 1000mL adds intermediate compound IV 81.0g (0.42mol) prepared by previous step, add toluene 500mL to dissolve, add 4-bromobutyrate 117g (0.6mol), add sodium carbonate 53.0g (0.5mol), heated and stirred refluxes, being incubated after reacting 24h, HPLC detection reaction substantially completely at 66-68 DEG C, reactant liquor is cooled to room temperature, filter, filtrate is intermediate III, and filtrate direct plunges into next step reaction, and HPLC detects purity 92.8%.
(3) preparation of intermediate II
The there-necked flask of 1000mL adds the intermediate III prepared of previous step, is subsequently adding sodium tert-butoxide 63.5g (0.66mol), heat to 66-68 DEG C anti-under reflux 5h. After HPLC detection reacts completely, reactant liquor cools down, and adding acetic acid 39g adjustment pH value is 7, reaction system proceeds to concentrating under reduced pressure in flask, adds ethyl acetate 500mL, tap water 200mL in concentrate, stirring layering, proceed in separatory funnel, organic layer washed with water, then dry, filter, filtrate concentrate grease is intermediate II (N-benzyl-3-oxo-piperidine-4-Ethyl formate) 92.3g, concentrate direct plunges into next step reaction, and the HPLC of concentrate detects purity 90.9%.
(4) preparation of target compound I
In the there-necked flask of 1000mL, add above-mentioned prepared intermediate II 92.3g (0.35mol), be subsequently adding the concentrated hydrochloric acid 230mL that concentration is 12mol/L, be heated to reflux 6h, t=86 DEG C-88 DEG C. HPLC detection reacts completely, reaction system is cooled to room temperature, reactant liquor rotation being steamed (68 DEG C) concentration anhydrate point and hydrogen chloride, concentrated solution is separately added into 150mL ethyl acetate, addition crystal seed, stirring and crystallizing 2-4h under room temperature, filter, collect off-white color filter cake, vacuum drying 4h at 80 DEG C, weigh target compound I (1-benzyl-3-piperidone hydrochloride) monohydrate 68.2g (yield 69.9%), HPLC detect purity 99.3%.
Claims (10)
1. the preparation method of a N-n-benzylglycine ethyl ester, it is characterised in that comprise the steps: to be dissolved in organic solvent I by benzylamine, be subsequently adding 2-halogenated acetic acids ethyl ester, alkali, quaternary ammonium salt, be obtained by reacting N-n-benzylglycine ethyl ester.
2. the preparation method of N-n-benzylglycine ethyl ester as claimed in claim 1, it is characterised in that described organic solvent I is selected from acetonitrile, dichloromethane, chloroform, carbon tetrachloride, oxolane, toluene or benzene; Described 2-halogenated acetic acids ethyl ester is 2-ethyl chloroacetate or 2-bromoethyl acetate; Described alkali is selected from triethylamine, diisopropylethylamine, pyridine, sodium carbonate or potassium carbonate; Described quaternary ammonium salt is selected from hydrogen sulfate TBuA, benzyltriethylammonium chloride or Dodecyl trimethyl ammonium chloride.
3. the preparation method of N-n-benzylglycine ethyl ester as claimed in claim 1, it is characterised in that described benzylamine, 2-halogenated acetic acids ethyl ester, alkali, quaternary ammonium salt mol ratio be 1:1��3:1��3:0.1��0.5.
4. the preparation method of a 1-benzyl-3-piperidone hydrochloride, it is characterised in that reaction equation is:
Concretely comprise the following steps:
(1) intermediate compound IV (N-n-benzylglycine ethyl ester) is prepared according to the method for claim 1 or 2 or 3;
(2) intermediate compound IV is dissolved in organic solvent II, is subsequently adding 4-halo ethyl n-butyrate., alkali, is obtained by reacting intermediate III;
(3) by described intermediate III and alkali reaction, regulating pH value after completion of the reaction is 6-8, concentrating under reduced pressure, and concentrated solution ethyl acetate is extracted, washing, dry, again concentrating under reduced pressure obtain intermediate II;
(4) by described intermediate II and acid reaction, after having reacted, rotation steaming obtains concentrated solution, adds recrystallisation solvent crystallization and obtain product in concentrated solution.
5. the preparation method of 1-benzyl-3-piperidone hydrochloride as claimed in claim 4, it is characterised in that in step 2, described organic solvent II is selected from chloroform, carbon tetrachloride, oxolane, toluene or benzene; Described 4-halo ethyl n-butyrate. is 4-chloro ethyl n-butyrate. or 4-bromobutyrate; Described alkali is selected from sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide or Lithium hydrate.
6. the preparation method of the 1-benzyl-3-piperidone hydrochloride as described in claim 4 or 5, it is characterised in that in step 2, described intermediate compound IV, 4-halo ethyl n-butyrate., alkali mol ratio be 1:1��2:1��3.
7. the preparation method of 1-benzyl-3-piperidone hydrochloride as claimed in claim 4, it is characterised in that in step 3, described alkali is selected from sodium tert-butoxide, potassium tert-butoxide, Sodium ethylate, potassium ethoxide, Feldalat NM or Feldalat KM.
8. the mol ratio of the preparation method of the 1-benzyl-3-piperidone hydrochloride as described in claim 4 or 7, it is characterised in that in step 3, described intermediate III and alkali is 1:1��3.
9. the preparation method of 1-benzyl-3-piperidone hydrochloride as claimed in claim 4, it is characterised in that in step 4, described acid is hydrochloric acid.
10. the preparation method of the 1-benzyl-3-piperidone hydrochloride as described in claim 4 or 9, it is characterised in that in step 4, described recrystallisation solvent is selected from acetonitrile, ethyl acetate or isopropanol; Described intermediate II is 1:3��10 with sour mol ratio.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110240561A (en) * | 2018-03-07 | 2019-09-17 | 新发药业有限公司 | A kind of preparation method of the 3- pyridone of low cost |
| CN110698356A (en) * | 2019-11-07 | 2020-01-17 | 南京恒远科技开发有限公司 | Preparation and purification method of N-benzyl glycine ethyl ester |
| CN110878042A (en) * | 2018-09-05 | 2020-03-13 | 新发药业有限公司 | Preparation method of N-substituent piperidine-3-ketone |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104910158A (en) * | 2015-06-15 | 2015-09-16 | 河南师范大学 | 5,6,7,8-tetrahydropyrido[3,4-d] pyrimidine compound with bioactivity as well as preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104910158A (en) * | 2015-06-15 | 2015-09-16 | 河南师范大学 | 5,6,7,8-tetrahydropyrido[3,4-d] pyrimidine compound with bioactivity as well as preparation method and application thereof |
Non-Patent Citations (1)
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| 刘明亮 等: "巴洛沙星的合成", 《中国医药工业杂志》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110240561A (en) * | 2018-03-07 | 2019-09-17 | 新发药业有限公司 | A kind of preparation method of the 3- pyridone of low cost |
| CN110240561B (en) * | 2018-03-07 | 2020-08-04 | 新发药业有限公司 | Low-cost preparation method of 3-hydroxypyridine |
| CN110878042A (en) * | 2018-09-05 | 2020-03-13 | 新发药业有限公司 | Preparation method of N-substituent piperidine-3-ketone |
| CN110878042B (en) * | 2018-09-05 | 2021-06-01 | 新发药业有限公司 | Preparation method of N-substituent piperidine-3-ketone |
| CN110698356A (en) * | 2019-11-07 | 2020-01-17 | 南京恒远科技开发有限公司 | Preparation and purification method of N-benzyl glycine ethyl ester |
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