CN102241626A - Synthesis process of flupirtine maleate - Google Patents
Synthesis process of flupirtine maleate Download PDFInfo
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Abstract
The invention relates to a preparation method of flupirtine maleate. The method comprises the following steps of: 1, synthesizing 2-amino-3-nitro-6-chloropyridine; 2, synthesizing 2-amino-3-nitro-6-[(4-luorobenzyl)amino] pyridine; 3, synthesizing 2,3-diamino-6-[(4-luorobenzyl)amino] pyridine; 4, synthesizing 2-amino-3-nitro-ethyl carbamate-6-[(4-luorobenzyl)amino] pyridine; 5, synthesizing 2-amino-6-[(4-luorobenzyl)amino] pyridine-3-ethyl carbamate maleate; and 6, refining flupirtine maleate.
Description
Technical field
The present invention relates to the new synthetic process of toxilic acid flupirtine, belong to the preparing technical field of medicinal chemicals.
Background technology
The toxilic acid flupirtine that the present invention relates to is the main component of preparation analgesic drug, its chemistry 2-amino by name-6-[(4-luorobenzyl) amino] pyridine-3-urethanum maleate, molecular formula: C
18H
21F
1N
4O
6Molecular weight: 420.4.
The synthetic route of the toxilic acid flupirtine of bibliographical information mainly contains following several method:
1, Von.Bebenburg is to the fluorophenyl bromine to be the synthetic NSC 158269 of starting raw material; take place to replace with 2-amino-3-nitro-6-chloropyridine again and generate intermediate 2-amino-3-nitro-6-fluorine benzyl aminopyridine; this intermediate is through catalytic hydrogenating reduction; generate the flupirtine hydrochloride with the Vinyl chloroformate selectively acylating; add the ammoniacal liquor neutralization then, with the toxilic acid salify.
2, Chot.Yong.M etc. is with 1; the 3-dibromopropane is the starting raw material Synthetic 2; 6-two chloro-3-nitropyridines; through 2 selectivity ammonia separate, 6 NSC 158269 replace Synthetic 2-amino-3-nitro-6-to fluorine benzyl aminopyridine; then behind the hydrogenating reduction filtration catalizer directly and Vinyl chloroformate generation acidylate get the flupirtine hydrochloride; through the ammoniacal liquor neutralization, last and toxilic acid salify.
3, in the process of synthetic flupirtine hydrochloride such as JoachimK.sevdclt; synthetic employing operate continuously to intermediate 2-amino-3-nitro-6-NSC 158269 yl pyridines; get the flupirtine hydrochloride with Vinyl chloroformate generation acidylate behind the hydrogenating reduction filtration catalizer, easy operation.
4, Orth.Winfried etc. has reported an other synthetic route.With 2-amino-3-nitro-6-methoxypyridine is starting raw material; generate 2-amino-3-nitro-6-to fluorine benzyl aminopyridine with NSC 158269 generation substitution reaction; yield is 95.2%, then behind the hydrogenating reduction filtration catalizer directly and Vinyl chloroformate generation acidylate get the flupirtine hydrochloride
5, Stefan Schwoch etc. has reported a new synthetic route.With the 2,3 diamino pyridine is starting raw material, with the pimelinketone condensation reaction, at MnO
2Existence down with the NSC 158269 linked reaction, reduction generates 2 then, 3-diamino-6-NSC 158269 yl pyridines, with the hydrochloride of Vinyl chloroformate generation selectively acylating reaction generation flupirtine, in the ammoniacal liquor with after become maleate again.
Comprehensive above synthesis technique, the synthetic route complicated operation of Von.Bebenburg etc., yield is very low, has influenced its industrial scale, has therefore restricted promoting the use of of toxilic acid flupirtine medicine.
Summary of the invention
The invention provides a kind of preparation method of new toxilic acid flupirtine, this method is through following steps:
1.2-amino-3-nitro-6-chloropyridine is synthetic
In reactor, squeeze into 500~1000mL Virahol, drop into 2 again, 6-two chloro-3-nitropyridines 50~100g, be stirred to complete molten after, 25 ℃ are stirred down and also feed ammonia, solution thickens gradually, generate yellow suspension liquid, react about 15~20h, the TLC monitoring reaction is stopped reaction fully.Filter, obtain yellow crystals.Filtrate is revolved steaming, obtains another part yellow crystals.Two portions yellow crystals is washed with 100~200mL water, and vacuum-drying gets product.mp?195-196℃。
2.2-amino amino-3-nitro-6-[(4-luorobenzyl)] pyridine synthetic
30~50g 2-amino-3-nitro-6-chloropyridine joins in the reactor, adds 500~1000mL Virahol again.Under the whipped state NSC 158269 30~50mL and triethylamine 70~80mL are dropped to respectively in the solution of previous step synthetic, the intensification 70-80 ℃ of 5~10h that refluxes, after the TLC monitoring reaction was complete, cooling was left standstill, and separates out crystal, filters, and obtains yellow crystals.Filtrate is revolved steaming, obtains another part yellow crystals.Two portions yellow crystals is washed with 100~200mL water, and vacuum-drying gets product.mp179~181℃。
3.2,3-diamino-6-[(4-luorobenzyl) and amino] pyridine synthetic
Add 2-amino-3-nitro-6-[(4-luorobenzyl in the autoclave) amino] pyridine 30~50g, Raney Ni 10~20g and Virahol 250~350mL fill hydrogen to 2~8MPa, 60~80 ℃ of down reactions are added H2 once, no longer descend to pressure, and then react 30~60min, reaction finishes.
4.2-amino amino-3-urethanum-6-[(4-luorobenzyl)] pyridine synthetic
. step 3 reacting liquid temperature is reduced at 30~35 ℃, and the quick down Vinyl chloroformate 10~20mL that adds is stirred in nitrogen protection, adds triethylamine 30~40mL, drips off the back and reacts 5~10h down at 30~40 ℃.
5.2-amino amino-6-[(4-luorobenzyl)] pyridine-3-urethanum maleate synthetic
. promptly have a large amount of light green solids to separate out to the aqueous isopropanol of 100~150mL toxilic acid, the 20~30g of whipped state step 4 reaction solution direct suction filtration under nitrogen protection, suction filtration gets product.mp165~170℃。
6. the process for refining of a toxilic acid flupirtine is characterized in that: take by weighing toxilic acid flupirtine 5.0g, add the Virahol of 60ml, reflux dissolving is treated the toxilic acid flupirtine all after the dissolving, cooling, add gac 1.5g, continue reflux, stop heating after 30 minutes, the filtering gac, get limpid filtrate, place crystallization in the refrigerator of back after the room temperature, filter after 5 hours toxilic acid flupirtine highly finished product, mp165-170 ℃.
The structural confirmation analysis of toxilic acid flupirtine
Test with the toxilic acid flupirtine sample that aforesaid method makes, the result is as follows:
Ultimate analysis: the elemental analysis of samples data of toxilic acid flupirtine
? | Theoretical value | The empirical average value |
C | 54.2835 | 54.29 |
H | 5.0350 | 5.00 |
N | 13.3273 | 13.10 |
The result of ultimate analysis and theoretical value basically identical.
Positively effect of the present invention is: following index all is better than prior art:
1, synthesis material obtains easily: 2,6-two chloro-3-nitropyridines are as the synthetic starting raw material of this technology, be commonly used for the raw material of synthetic medicine, dyestuff, resin, can produce fertilizer synergistic agent, weedicide, livestock wormer, rubber accelerator, dyestuff intermediate etc., have purposes widely.Therefore on market, be easy to buy, cheap, and also purity can reach more than 98%.
2, yield height: such as: the total recovery of first two steps reaction can reach 90.02% in this technology, and other technology first two steps yields of bibliographical information are about 85.1%.
3, easy control of reaction conditions: this technology mesohigh hydrogenation temperature is controlled at 65 ℃, and other technologies of bibliographical information, under uniform pressure, the hydrogenant temperature then needs to reach 70~80 ℃.As seen this Technology provides more favourable reaction conditions for suitability for industrialized production, can reduce the requirement of conversion unit greatly, more helps being applied to suitability for industrialized production.
In sum, the present invention is applicable to suitability for industrialized production, in clinical, has bigger social benefit and economic benefit with the medicinal application of its preparation.
Embodiment
Embodiment 1
1.2-amino-3-nitro-6-chloropyridine is synthetic
In reactor, squeeze into the 500mL Virahol, drop into 2 again, 6-two chloro-3-nitropyridine 50g, be stirred to complete molten after, 25 ℃ are stirred down and also feed ammonia, solution thickens gradually, generates yellow suspension liquid, reacts about 20h, the TLC monitoring reaction is stopped reaction fully.Filter, obtain yellow crystals.Filtrate is revolved steaming, obtains another part yellow crystals.Two portions yellow crystals is washed with 100mL water, and drying obtains product 44.3g, yield 98.5%.mp179~181℃。
2.2-amino amino-3-nitro-6-[(4-luorobenzyl)] pyridine synthetic
45g 2-amino-3-nitro-6-chloropyridine joins in the reactor, adds the 500mL Virahol again.Under the whipped state NSC 158269 45mL and triethylamine 75mL are dropped to respectively in the solution of previous step synthetic, the 75 ℃ of backflow 5h that heat up, after the TLC monitoring reaction was complete, cooling was left standstill, and separates out crystal, filters, and obtains yellow crystals.Filtrate is revolved steaming, obtains another part yellow crystals.Two portions yellow crystals is washed with 100mL water, and drying obtains product 45.7g, yield 91.4%.mp179~181℃。
3.2,3-diamino-6-[(4-luorobenzyl) and amino] pyridine synthetic
Add 2-amino-3-nitro-6-[(4-luorobenzyl in the autoclave) amino] pyridine 40g, Raney Ni 15g and Virahol 300mL fill hydrogen to 4MPa, and H is added in 65 ℃ of reactions down
2Once, no longer descend to pressure, and then reaction 45min, reaction finishes.
4.2-amino amino-3-urethanum-6-[(4-luorobenzyl)] pyridine synthetic
. above-mentioned reacting liquid temperature is reduced at 30~35 ℃, and the quick down Vinyl chloroformate 14mL that adds is stirred in nitrogen protection, adds triethylamine 40mL, drips off the back and reacts 5h down at 35 ℃.
5.2-amino amino-6-[(4-luorobenzyl)] pyridine-3-urethanum maleate synthetic
With reaction solution of last step under nitrogen protection directly suction filtration to the aqueous isopropanol of the 120mL toxilic acid 22g of whipped state; promptly there are a large amount of light green solids to separate out; suction filtration goes out the toxilic acid flupirtine; with twice in Virahol recrystallization; activated carbon decolorizing; 35 ℃ of following vacuum-dryings obtain toxilic acid flupirtine highly finished product 28.3g.Productive rate 70.6%, purity 99.7%.mp165~170℃。
Embodiment 2
The toxilic acid flupirtine is refining
Take by weighing toxilic acid flupirtine 5.0g, add the 60ml Virahol, the reflux dissolving, after treating that the toxilic acid flupirtine all dissolves, cooling adds gac 1.5g, continues reflux, stop heating after 30 minutes, the filtering gac gets limpid filtrate, crystallization in the refrigerator of back after the placement room temperature, filter after 5 hours toxilic acid flupirtine highly finished product 3.5g, mp165-170 ℃.
Claims (2)
1. the synthesis technique of a toxilic acid flupirtine may further comprise the steps:
1) 2-amino-3-nitro-6-chloropyridine is synthetic
In reactor, squeeze into 500~1000mL Virahol, drop into 2 again, 6-two chloro-3-nitropyridines 50~100g, be stirred to complete molten after, 25 ℃ are stirred down and also feed ammonia, solution thickens gradually, generate yellow suspension liquid, react about 15~20h, the TLC monitoring reaction is stopped reaction fully, filter, obtain yellow crystals, filtrate is revolved steaming, obtain another part yellow crystals, two portions yellow crystals is washed with 100~200mL water, and vacuum-drying gets product;
2) amino 2-amino-3-nitro-6-[(4-luorobenzyl)] pyridine synthetic
30~50g 2-amino-3-nitro-6-chloropyridine joins in the reactor, add 500~1000mL Virahol again, under the whipped state NSC 158269 30~50mL and triethylamine 70~80mL are dropped to respectively in the solution of previous step synthetic, the intensification 70-80 ℃ of 5~10h that refluxes, after the TLC monitoring reaction is complete, cooling, leave standstill, separate out crystal, filter, obtain yellow crystals, filtrate is revolved steaming, obtains another part yellow crystals, and two portions yellow crystals is washed with 100~200mL water, vacuum-drying gets product;
3) amino 2,3-diamino-6-[(4-luorobenzyl)] pyridine synthetic
Add 2-amino-3-nitro-6-[(4-luorobenzyl in the autoclave) amino] pyridine 30~50g, Raney Ni 10~20g and Virahol 250~350mL, logical hydrogen to 2~8MPa, 60~80 ℃ of down reactions are added hydrogen once, no longer descend to pressure, and then react 30~60min, reaction finishes;
4) amino 2-amino-3-urethanum-6-[(4-luorobenzyl)] pyridine synthetic
Step 3 reacting liquid temperature is reduced at 30~35 ℃, and the quick down Vinyl chloroformate 10~20mL that adds is stirred in nitrogen protection, adds triethylamine 20~40mL, drips off the back and reacts 5~10h down at 30~40 ℃;
5) amino 2-amino-6-[(4-luorobenzyl)] pyridine-3-urethanum maleate synthetic
Promptly have a large amount of light green solids to separate out to the aqueous isopropanol of 20~30g toxilic acid, the 100~150mL of whipped state step 4 reaction solution direct suction filtration under nitrogen protection, suction filtration gets product;
6) refining
Take by weighing toxilic acid flupirtine 5.0g, add the Virahol of 60ml, the reflux dissolving, after treating that the toxilic acid flupirtine all dissolves, cooling adds gac 1.5g, continues reflux, stop heating after 30 minutes, the filtering gac gets limpid filtrate, crystallization in the refrigerator of back after the placement room temperature, 5 hours after-filtration get toxilic acid flupirtine highly finished product.
2. the synthesis technique of claim 1 may further comprise the steps:
1) 2-amino-3-nitro-6-chloropyridine is synthetic
In reactor, squeeze into the 500mL Virahol, drop into 2 again, 6-two chloro-3-nitropyridine 50g, be stirred to complete molten after, 25 ℃ are stirred down and also feed ammonia, solution thickens gradually, generates yellow suspension liquid, reacts about 20h, the TLC monitoring reaction is stopped reaction fully; Filter, obtain yellow crystals; Filtrate is revolved steaming, obtains another part yellow crystals, and two portions yellow crystals is washed with 100mL water, and drying obtains product 44.3g, yield 98.5%, mp179~181 ℃;
2) amino 2-amino-3-nitro-6-[(4-luorobenzyl)] pyridine synthetic
45g 2-amino-3-nitro-6-chloropyridine joins in the reactor, add the 500mL Virahol again, under the whipped state NSC 158269 45mL and triethylamine 75mL are dropped to respectively in the solution of previous step synthetic, 75 ℃ of backflow 5h heat up, after the TLC monitoring reaction was complete, cooling was left standstill, separate out crystal, filter, obtain yellow crystals, filtrate is revolved steaming, obtain another part yellow crystals, two portions yellow crystals is washed with 100mL water, and drying obtains product 45.7g, yield 91.4%, mp179~181 ℃;
3) amino 2,3-diamino-6-[(4-luorobenzyl)] pyridine synthetic
Add 2-amino-3-nitro-6-[(4-luorobenzyl in the autoclave) amino] pyridine 40g, Raney Ni 15g and Virahol 300mL fill hydrogen to 4MPa, and H is added in 65 ℃ of reactions down
2Once, no longer descend to pressure, and then reaction 45min, reaction finishes;
4) amino 2-amino-3-urethanum-6-[(4-luorobenzyl)] pyridine synthetic
Above-mentioned reacting liquid temperature is reduced at 30~35 ℃, and the quick down Vinyl chloroformate 14mL that adds is stirred in nitrogen protection, adds triethylamine 40mL, drips off the back and reacts 5h down at 35 ℃;
5) amino 2-amino-6-[(4-luorobenzyl)] pyridine-3-urethanum maleate synthetic
With reaction solution of last step under nitrogen protection directly suction filtration to the aqueous isopropanol of the 120mL toxilic acid 22g of whipped state, promptly there are a large amount of light green solids to separate out, suction filtration goes out the toxilic acid flupirtine, with twice in Virahol recrystallization, activated carbon decolorizing, 35 ℃ of following vacuum-dryings obtain toxilic acid flupirtine highly finished product 28.3g; Productive rate 70.6%, purity 99.7%, mp165~170 ℃.
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102838534A (en) * | 2012-10-10 | 2012-12-26 | 苏州二叶制药有限公司 | Preparation method of flupirtine maleate |
CN103333103A (en) * | 2013-07-12 | 2013-10-02 | 南京正大天晴制药有限公司 | Method for preparing flupirtine maleate by one-pot method |
CN104086481A (en) * | 2014-07-18 | 2014-10-08 | 四川新斯顿制药有限责任公司 | Synthesis method of flupirtine maleate |
CN104974087A (en) * | 2015-01-30 | 2015-10-14 | 吉林修正药业新药开发有限公司 | Synthesis method of flupirtine dimer |
CN106397313A (en) * | 2016-08-31 | 2017-02-15 | 安徽省润生医药股份有限公司 | High efficient synthesis method of flupirtine maleate |
CN109053563A (en) * | 2018-07-20 | 2018-12-21 | 四川青木制药有限公司 | A method of preparing hydrochloric acid Flupirtine |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3481943A (en) * | 1966-05-12 | 1969-12-02 | Degussa | Benzyl and pyridylmethyl substituted amido amino pyridines |
BE764362R (en) * | 1966-05-12 | 1971-09-16 | Degussa | Subst amino pyridienes production |
US3809695A (en) * | 1967-04-19 | 1974-05-07 | Degussa | 2,6-dichloro-3-nitro-pyridine |
DE1795797A1 (en) * | 1967-04-19 | 1975-08-28 | Degussa | REPRODUCTION PRODUCTS OF 2,6DICHLORO-3-NITRO-PYRIDINE |
US4481205A (en) * | 1980-09-13 | 1984-11-06 | Degussa Aktiengesellschaft | 2-Amino-3-carbethoxyamino-6-(p-fluoro-benzylamino)-pyridine-maleate |
WO2010136113A1 (en) * | 2009-05-29 | 2010-12-02 | Corden Pharmachem Gmbh | Method for producing flupirtine |
-
2011
- 2011-05-03 CN CN 201110112934 patent/CN102241626B/en active Active
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3481943A (en) * | 1966-05-12 | 1969-12-02 | Degussa | Benzyl and pyridylmethyl substituted amido amino pyridines |
BE764362R (en) * | 1966-05-12 | 1971-09-16 | Degussa | Subst amino pyridienes production |
US3809695A (en) * | 1967-04-19 | 1974-05-07 | Degussa | 2,6-dichloro-3-nitro-pyridine |
DE1795797A1 (en) * | 1967-04-19 | 1975-08-28 | Degussa | REPRODUCTION PRODUCTS OF 2,6DICHLORO-3-NITRO-PYRIDINE |
US4481205A (en) * | 1980-09-13 | 1984-11-06 | Degussa Aktiengesellschaft | 2-Amino-3-carbethoxyamino-6-(p-fluoro-benzylamino)-pyridine-maleate |
WO2010136113A1 (en) * | 2009-05-29 | 2010-12-02 | Corden Pharmachem Gmbh | Method for producing flupirtine |
Non-Patent Citations (1)
Title |
---|
YONG M. CHOI ET AL: "A NINE-STEP SYNTHESIS OF [14C]FLUPIRTINE MALEATE LABELED IN THE PYRIDINE RING", 《JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS》, no. 1, 31 December 1986 (1986-12-31), pages 1 - 14, XP002485789, DOI: doi:10.1002/jlcr.2580240102 * |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102838534A (en) * | 2012-10-10 | 2012-12-26 | 苏州二叶制药有限公司 | Preparation method of flupirtine maleate |
CN103333103A (en) * | 2013-07-12 | 2013-10-02 | 南京正大天晴制药有限公司 | Method for preparing flupirtine maleate by one-pot method |
CN103333103B (en) * | 2013-07-12 | 2015-07-22 | 南京正大天晴制药有限公司 | Method for preparing flupirtine maleate by one-pot method |
CN104086481A (en) * | 2014-07-18 | 2014-10-08 | 四川新斯顿制药有限责任公司 | Synthesis method of flupirtine maleate |
CN104974087A (en) * | 2015-01-30 | 2015-10-14 | 吉林修正药业新药开发有限公司 | Synthesis method of flupirtine dimer |
CN106397313A (en) * | 2016-08-31 | 2017-02-15 | 安徽省润生医药股份有限公司 | High efficient synthesis method of flupirtine maleate |
CN109053563A (en) * | 2018-07-20 | 2018-12-21 | 四川青木制药有限公司 | A method of preparing hydrochloric acid Flupirtine |
CN109053563B (en) * | 2018-07-20 | 2022-03-29 | 四川青木制药有限公司 | Method for preparing flupirtine hydrochloride |
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