CN105884762A - (3aR,9bS)-tert-butyl-3,3a,5,9b-tetrahydro-1hydrogen-pyrrole[3,4-c]isoquinoline-4(2hydrogen)-carboxylic ester - Google Patents
(3aR,9bS)-tert-butyl-3,3a,5,9b-tetrahydro-1hydrogen-pyrrole[3,4-c]isoquinoline-4(2hydrogen)-carboxylic ester Download PDFInfo
- Publication number
- CN105884762A CN105884762A CN201410185144.9A CN201410185144A CN105884762A CN 105884762 A CN105884762 A CN 105884762A CN 201410185144 A CN201410185144 A CN 201410185144A CN 105884762 A CN105884762 A CN 105884762A
- Authority
- CN
- China
- Prior art keywords
- compound
- reaction
- hydrogen
- tert
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention relates to a preparation method of (3aR,9bS)-tert-butyl-3,3a,5,9b-tetrahydro-1hydrogen-pyrrole[3,4-c]isoquinoline-4(2hydrogen)-carboxylic ester. The technical problem that there is no method suitable for industrial synthesis of the above compound at present is mainly solved. The preparation method comprises the following seven steps: Step 1, a compound 1 and nitromethane react under the alkaline condition to obtain a compound 2; Step 2, the compound 2 and dimethyl carbonate react to obtain a compound 3; Step 3, a [3+2] reaction between the compound 3 and a compound 8 is carried out to obtain a compound 4; Step 4, the compound 4 undergoes raney nickel reduction and the product directly reacts with MeONa to obtain a compound 5; Step 5, the compound 5 undergoes LiAlH reduction to obtain a compound 6; Step 6, the compound 6 reacts with Boc anhydride to obtain a compound 7; and Step 7, hydrogenation debenzylation is finally carried out to obtain the final product, namely a compound 9. The compound obtained by the preparation method is a useful intermediate or a product synthesized by many medicines.
Description
Technical field
The present invention relates to the synthetic method of (3aR, 9bS)-tert-butyl group-3,3a, 5,9b-tetrahydrochysene-1 hydrogen-pyrroles [3,4-c] isoquinolin-4 (2 hydrogen)-carboxylate (CAS:1251002-37-5).
Background technology
(3aR, 9bS)-tert-butyl group-3,3a, 5,9b-tetrahydrochysene-1 hydrogen-pyrroles [3,4-c] isoquinolin-4 (2 hydrogen)-carboxylate and relevant derivant have in pharmaceutical chemistry and organic synthesis and are widely used.At present about (3aR, 9bS)-tert-butyl group-3,3a, 5, the synthesis of 9b-tetrahydrochysene-1 hydrogen-pyrroles [3,4-c] isoquinolin-4 (2 hydrogen)-carboxylate does not also have document to report, similar document use sodium azide to reset after intramolecular cyclization again, reaction there is certain danger and route is long, and yield is relatively low.Accordingly, it would be desirable to one raw material of exploitation is easy to get, easy to operate, react easily controllable, the synthetic method that overall yield is suitable for.
Summary of the invention
It is an object of the invention to develop one there is raw material be easy to get, easy to operate, react easily controllable, (3aR, the 9bS)-tert-butyl group-3 that yield is higher, 3a, the synthetic method of 5,9b-tetrahydrochysene-1 hydrogen-pyrroles [3,4-c] isoquinolin-4 (2 hydrogen)-carboxylate.Mainly solve the technical problem currently without applicable Industrialized synthesis method.
Technical scheme: a kind of (3aR, the 9bS)-tert-butyl group-3,3a, the preparation method of 5,9b-tetrahydrochysene-1 hydrogen-pyrroles [3,4-c] isoquinolin-4 (2 hydrogen)-carboxylate, comprises the following steps, and the present invention divides seven steps, first compound1React under the conditions of sodium hydroxide solution with nitromethane and obtain compound2, then with dimethyl carbonate under potassium carbonate effect in acetone back flow reaction obtain compound3, then with compound8Under trifluoroacetic acid effect, carry out [3+2] reaction obtain compound4, compound4After Raney's nickel (Raney Ni) reduces directly and Feldalat NM effect obtains compound5, the reduction of the most hydrogenated aluminum lithium obtains compound6, then obtain compound with Boc anhydride reaction7, the de-benzyl of finally hydrogenation obtains finished product compound9, reaction equation is as follows:
In above-mentioned reaction, first step reaction nitromethane consumption 1 equivalent；Three-step reaction compound 8 consumption 1 equivalent.
Beneficial effects of the present invention: the invention provides a kind of synthesis (3aR, the 9bS)-tert-butyl group-3,3a, 5,9b-tetrahydrochysene-1 hydrogen-pyrroles [3,4-c] method of isoquinolin-4 (2 hydrogen)-carboxylate, the use of a large amount of sodium azide is avoided by introducing nitro, the method route is short, yield may be up to 6.9%, reaction is prone to amplify, easy to operate, has industrial applications prospect.
Detailed description of the invention
Reaction equation of the present invention is as follows:
Embodiment 1:a, by compound1(50 g, 0.33 mol) and nitromethane (44 mL,
0.80 mol) it is dissolved in methanol (400 mL), at-10 DEG C to 10 DEG C, drip sodium hydrate aqueous solution (5M-15M, 100 mL).Reaction system stirs 1 hour at 15 DEG C to 30 DEG C.TLC (petrol ether/ethyl acetate=2:1, volume ratio, lower same) show that reaction terminates.Reaction system is 10 DEG C to 20 DEG C of droppings HCl/water solution (4M-8M, 800 mL).Reaction system is cooled to 5 DEG C to 10 DEG C, has a large amount of white solid to separate out, after being collected by filtration, wash with a small amount of clear water, be placed in vacuum drying oven and be dried, obtain compound as white solid2(64 g), yield 100%.
δ 7.780-7.760 (m, 1H),
7.581-7.603 (m, 1H), 7.501-7.488 (m, 1H), 7.480- 7.469 (m, 1H), 5.301-5.103 (m,
2H), 5.260-5.253 (m, 1H)。
B, by compound2(73 g, 0.38 mol) and potassium carbonate (89 g, 0.64 mol) are dissolved in acetone (500 mL), dimethyl carbonate (81 g, 0.9 mol) are added drop-wise in this reaction system at 10 DEG C to 20 DEG C.This reaction system stirs 4-6 hour under the conditions of 20 DEG C to 30 DEG C afterwards.TLC (petrol ether/ethyl acetate=3/1) display reaction terminates.With dichloromethane (200mLx3) extraction after reactant liquor use water (500mL) dilution.Combined dichloromethane uses Na the most afterwards2SO4Being dried, the crude product after concentration obtains compound through column chromatography purification (petrol ether/ethyl acetate=40/1 to 20/1)3(20 g), yield 26%.
δ 8.13 (s, 1H), 8.011-7.989
(m, 1H), 7.97 (s, 1H), 7.651-7.599 (m, 1H), 7.501-7.489 (m, 1H), 7.456-7.438
(m, 1H), 3.900 (s, 3H)。
C, by compound 3 (20 g, 97 mmol) it is dissolved in dichloromethane (200 mL) with compound 8 (25 g, 106 mmol), control reaction system at-10 DEG C to 10 DEG C, dropping TFA (2.2 g, 19 mmol).After end, reaction system stirs 16 hours at 20 DEG C to 30 DEG C.TLC (petrol ether/ethyl acetate=5/1) display reaction terminates.Reaction system use water (100 mL) washs, and then uses Na2SO4It is dried, after filtration, is concentrated to give thick product.Compound is obtained through column chromatography purification (petrol ether/ethyl acetate=40/1 to 20/1)4(17.3 g), yield 53%.
δ 7.771-7.758 (m, 1H),
7.592-7.578 (m, 1H), 7.416-7.408 (m, 1H), 7.385-7.379 (m, 1H), 7.350-7.231 (m,
5H), 4.302-4.300 (m, 1H), 4.012 (s, 2H), 3.900 (s, 3H), 3.011-2.992 (m, 2H),
2.761-2.505 (m, 3H)。
D, by compound4(15.3 g, 45 mmol) and Raney Ni (5 g) are placed in methanol (200 mL), and at 30 DEG C to 80 DEG C, hydrogenation (30Psi to 50Psi) reacts 16 hours.TLC (petrol ether/ethyl acetate=3/1) display reaction terminates.After reaction system is removed Hydrogen Vapor Pressure, add NaOMe (4.9 g, 90 mmol) and react 2 hours at 50 DEG C to 80 DEG C.Reaction system being filtered through diatomite layer, filtrate obtains compound after concentrating5Crude product, be directly used in next step reaction.
E, by LiAlH4(3.4 g, 90 mmol) are suspended in oxolane (80 mL), and the lower temperature that controls of nitrogen protection, at-10 DEG C to 10 DEG C, drips compound5Oxolane (50 mL) solution of (12.5 g, 45 mmol).Afterwards, reaction system is heated to reflux state, maintains 3 hours to 6 hours.TLC (methylene chloride/methanol=10/1) display reaction terminates.Reaction system is cooled to 10 DEG C, is slowly added to water (3.4 mL) and mass percentage concentration is 10% NaOH
Aqueous solution (6.8 mL), then filters.Filter cake dichloromethane washs three times.It is concentrated to give compound after filtrate being merged6Crude product, and be directly used in next step reaction.
F, by compound6It is dissolved in dichloromethane (200mL) with triethylamine (9.1 g, 90 mmol), at 0 DEG C to 10 DEG C, drips Boc anhydride (10.2 g, 49 mmol).Reaction system stirs 16 lab scales at 20 DEG C to 30 DEG C.TLC (petrol ether/ethyl acetate=3/1) display reaction terminates.Reaction system, after water (100 mL) washs, is dried and is concentrated to give crude product, obtain the compound of white solid through column chromatography purification (petrol ether/ethyl acetate=15/1 to 5/1)7(10.9 g), d, e, f tri-step total recovery 66%.
δ7.501-7.302 (m, 5H),
7.302-7.288 (m, 3H), 7.089-7.072 (m, 1H), 4.953 (s, 1H), 4.346-4.309 (d, J =
14.8, 1H), 4.020 (m, 2H), 3.745 (s, 1H), 3.593-3.554 (m, 2H), 3.269-3.254 (m,
2H), 3.241-3.230 (m, 1H), 3.218-2.955 (m, 1H), 1.958 (s, 1H), 1.500 (s, 9H)。
G, by compound7(10.9 g, 30 mmol) and palladium-carbon catalyst (4 g) are placed in methanol (150 mL), and at 25 DEG C to 60 DEG C, hydrogenation (15Psi to 50Psi) reacts 16 hours.TLC (petrol ether/ethyl acetate=1/1) display reaction terminates.Reaction system filters through diatomite layer, and filtrate obtains finished product compound after concentrating9(6.2 g), yield 76%.
δ7.302-7.288 (m, 3H),
7.089-7.072 (m, 1H), 4.953 (s, 1H), 4.346-4.309 (d, J = 14.8, 1H), 3.745 (s,
1H), 3.593-3.554 (m, 2H), 3.269-3.254 (m, 2H), 3.241-3.230 (m, 1H), 3.218-2.955
(m, 1H), 1.958 (s, 1H), 1.500 (s, 9H)。
Embodiment 2:a, by compound1(200 g, 1.323 mol) and nitromethane (176 mL,
3.2 mol) it is dissolved in methanol (1.6 L), at-10 DEG C to 10 DEG C, drip NaOH aqueous solution (5M-15M, 400 mL).Reaction system stirs 1 hour at 15 DEG C to 30 DEG C.TLC (petrol ether/ethyl acetate=2:1) display reaction terminates.Reaction system is 10 DEG C to 20 DEG C of droppings HCl/water solution (4M-8M, 3.2 L).Reaction system is cooled to 5 DEG C to 10 DEG C, has a large amount of white solid to separate out, after being collected by filtration, wash with a small amount of clear water, be placed in vacuum drying oven and be dried, obtain compound as white solid2(264 g), yield 100%.
δ 7.780-7.760 (m, 1H),
7.581-7.603 (m, 1H), 7.501-7.488 (m, 1H), 7.480- 7.469 (m, 1H), 5.301-5.103 (m,
2H), 5.260-5.253 (m, 1H)。
B, by compound2(292 g, 1.52 mol) and K2CO3(356
G, 2.56 mol) it is dissolved in acetone (2.0 L), dimethyl carbonate (324 g, 3.6 mol) is added drop-wise in this reaction system at 10 DEG C to 20 DEG C.This reaction system stirs 4-6 hour under the conditions of 20 DEG C to 30 DEG C afterwards.TLC (petrol ether/ethyl acetate=3/1) display reaction terminates.With dichloromethane (800mLx3) extraction after reactant liquor use water (2.0 L) dilution.Combined dichloromethane uses Na the most afterwards2SO4Being dried, the crude product after concentration obtains compound through column chromatography purification (petrol ether/ethyl acetate=40/1 to 20/1)3(80 g), yield 26%.
δ 8.13 (s, 1H), 8.011-7.989
(m, 1H), 7.97 (s, 1H), 7.651-7.599 (m, 1H), 7.501-7.489 (m, 1H), 7.456-7.438
(m, 1H), 3.900 (s, 3H)。
C, by compound 3 (80 g, 0.38 mol) it is dissolved in dichloromethane (800 mL) with compound 8 (100 g, 0.42 mol), control reaction system at-10 DEG C to 10 DEG C, dropping TFA (8.8 g, 76 mmol).After end, reaction system stirs 16 hours at 20 DEG C to 30 DEG C.TLC (petrol ether/ethyl acetate=5/1) display reaction terminates.Reaction system use water (400 mL) washs, and then uses Na2SO4It is dried, after filtration, is concentrated to give thick product.Compound is obtained through column chromatography purification (petrol ether/ethyl acetate=40/1 to 20/1)4(69.2 g), yield 53%.
δ 7.771-7.758 (m, 1H),
7.592-7.578 (m, 1H), 7.416-7.408 (m, 1H), 7.385-7.379 (m, 1H), 7.350-7.231 (m,
5H), 4.302-4.300 (m, 1H), 4.012 (s, 2H), 3.900 (s, 3H), 3.011-2.992 (m, 2H),
2.761-2.505 (m, 3H)。
D, by compound4(61.2 g, 180 mmol) and Raney Ni (10 g) are placed in methanol (800 mL), and at 30 DEG C to 80 DEG C, hydrogenation (30Psi to 50Psi) reacts 16 hours.TLC (petrol ether/ethyl acetate=3/1) display reaction terminates.After reaction system is removed Hydrogen Vapor Pressure, add NaOMe (4.9 g, 90 mmol) and react 2 hours at 50 DEG C to 80 DEG C.Reaction system being filtered through diatomite layer, filtrate obtains compound after concentrating5Crude product, be directly used in next step reaction.
E, by LiAlH4(13.6 g, 0.36 mol) is suspended in oxolane (320 mL), and the lower temperature that controls of nitrogen protection, at-10 DEG C to 10 DEG C, drips compound5Oxolane (200 mL) solution.Afterwards, reaction system is heated to reflux state, maintains 3 hours to 6 hours.TLC (methylene chloride/methanol=10/1) display reaction terminates.Reaction system is cooled to 10 DEG C, is slowly added to water (13.6 mL) and mass percentage concentration is 10% NaOH
Aqueous solution (27.2 mL), then filters.Filter cake dichloromethane washs three times.It is concentrated to give compound after filtrate being merged6Crude product, and be directly used in next step reaction.
F, by compound6It is dissolved in dichloromethane (800mL) with triethylamine (36.4 g, 0.36 mol), at 0 DEG C to 10 DEG C, drips Boc anhydride (40.4 g, 196 mmol).Reaction system stirs 16 lab scales at 20 DEG C to 30 DEG C.TLC (petrol ether/ethyl acetate=3/1) display reaction terminates.Reaction system, after water (100 mL) washs, is dried and is concentrated to give crude product, obtain the compound of white solid through column chromatography purification (petrol ether/ethyl acetate=15/1 to 5/1)7(43.6 g), d, e, f tri-step total recovery 66%.
δ7.501-7.302 (m, 5H),
7.302-7.288 (m, 3H), 7.089-7.072 (m, 1H), 4.953 (s, 1H), 4.346-4.309 (d, J =
14.8, 1H), 4.020 (m, 2H), 3.745 (s, 1H), 3.593-3.554 (m, 2H), 3.269-3.254 (m,
2H), 3.241-3.230 (m, 1H), 3.218-2.955 (m, 1H), 1.958 (s, 1H), 1.500 (s, 9H)。
G, by compound7(43.6 g, 0.12 mol) and Pd/C (10 g) are placed in methanol (600 mL), and at 25 DEG C to 60 DEG C, hydrogenation (15Psi to 50Psi) reacts 16 hours.TLC (petrol ether/ethyl acetate=1/1) display reaction terminates.Reaction system filters through diatomite layer, and filtrate obtains finished product compound after concentrating9(24.8 g), yield 76%.
δ7.302-7.288 (m, 3H),
7.089-7.072 (m, 1H), 4.953 (s, 1H), 4.346-4.309 (d, J = 14.8, 1H), 3.745 (s,
1H), 3.593-3.554 (m, 2H), 3.269-3.254 (m, 2H), 3.241-3.230 (m, 1H), 3.218-2.955
(m, 1H), 1.958 (s, 1H), 1.500 (s, 9H)。
Claims (2)
1. (3aR, the 9bS)-tert-butyl group-3,3a, the preparation method of 5,9b-tetrahydrochysene-1 hydrogen-pyrroles [3,4-c] isoquinolin-4 (2 hydrogen)-carboxylate, it is characterized in that comprising the following steps: first, compound1React under the conditions of sodium hydroxide solution with nitromethane and obtain compound2, compound 2 and dimethyl carbonate obtain compound3, then compound 3 and compound8Carry out [3+2] reaction and obtain compound4, compound4After Raney's nickel reduces directly and Feldalat NM effect obtains compound5, the reduction of compound 5 hydrogenated aluminum lithium obtains compound6, then compound 6 and Boc anhydride reaction obtain compound7, the de-benzyl of final compound 7 hydrogenation obtains finished product compound9, reaction equation is as follows:
。
One the most according to claim 1 (3aR, the 9bS)-tert-butyl group-3,3a, 5, the preparation method of 9b-tetrahydrochysene-1 hydrogen-pyrroles [3,4-c] isoquinolin-4 (2 hydrogen)-carboxylate, is characterized in that first step reaction nitromethane consumption is 1 equivalent；Three-step reaction compound 8 consumption is 1 equivalent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410185144.9A CN105884762A (en) | 2014-05-05 | 2014-05-05 | (3aR,9bS)-tert-butyl-3,3a,5,9b-tetrahydro-1hydrogen-pyrrole[3,4-c]isoquinoline-4(2hydrogen)-carboxylic ester |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410185144.9A CN105884762A (en) | 2014-05-05 | 2014-05-05 | (3aR,9bS)-tert-butyl-3,3a,5,9b-tetrahydro-1hydrogen-pyrrole[3,4-c]isoquinoline-4(2hydrogen)-carboxylic ester |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105884762A true CN105884762A (en) | 2016-08-24 |
Family
ID=56999810
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410185144.9A Pending CN105884762A (en) | 2014-05-05 | 2014-05-05 | (3aR,9bS)-tert-butyl-3,3a,5,9b-tetrahydro-1hydrogen-pyrrole[3,4-c]isoquinoline-4(2hydrogen)-carboxylic ester |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105884762A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108864088A (en) * | 2018-08-01 | 2018-11-23 | 河南湾流生物科技有限公司 | The preparation method of novel isoquinoline drug molecule with antibacterial activity |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060014778A1 (en) * | 2004-07-14 | 2006-01-19 | Fevig John M | Pyrrolo(oxo)quinolines as 5HT ligands |
| CN103073547A (en) * | 2013-02-06 | 2013-05-01 | 上海药明康德新药开发有限公司 | Synthesis method of (3aS, 9bR)-tert-butyl-3,3 a, 4,5-tetrahydro-pyrrolo [3,4-c] quinolin-2 (9bH) ester |
-
2014
- 2014-05-05 CN CN201410185144.9A patent/CN105884762A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060014778A1 (en) * | 2004-07-14 | 2006-01-19 | Fevig John M | Pyrrolo(oxo)quinolines as 5HT ligands |
| CN103073547A (en) * | 2013-02-06 | 2013-05-01 | 上海药明康德新药开发有限公司 | Synthesis method of (3aS, 9bR)-tert-butyl-3,3 a, 4,5-tetrahydro-pyrrolo [3,4-c] quinolin-2 (9bH) ester |
Non-Patent Citations (3)
| Title |
|---|
| AMERICAN CHEMICAL SOCIETY: "RN1251002-37-5", 《REGISTRY》 * |
| BARTLETT D.WHELTON等: "3-Nitromethylphthalide and 2-Phenyl-3-nitromethylphthalimidine", 《J.ORG.CHEM.》 * |
| JEAN-MARIE FERLAND等: "Synthesis of derivatives of isoindole and of pyrazino[2,1-a]isoindole", 《CAN. J . CHEM.》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108864088A (en) * | 2018-08-01 | 2018-11-23 | 河南湾流生物科技有限公司 | The preparation method of novel isoquinoline drug molecule with antibacterial activity |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107383026B (en) | A kind of synthetic method of 7- methylol -2,5- diaza spiro [3,4] octane -2- t-butyl formate | |
| CN102351735A (en) | Preparation method of Iopromide | |
| CN106916111A (en) | A kind of (S) -2- methyl isophthalic acids, the synthetic method of 4,5,6- tetrahydrochysene methylpyrimidine -4- carboxylic acids | |
| CN105884762A (en) | (3aR,9bS)-tert-butyl-3,3a,5,9b-tetrahydro-1hydrogen-pyrrole[3,4-c]isoquinoline-4(2hydrogen)-carboxylic ester | |
| CN109824547A (en) | A kind of synthetic method of double different protected amino acids | |
| CN103880745B (en) | A kind of chemical synthesis process of the bromo- 1,2,3,4- tetrahydroisoquinoline -1- formic acid of 6- | |
| CN104130262A (en) | Ertapenem and ertapenem side chain, as well as preparation methods of ertapenem and ertapenem side chains | |
| CN103159620A (en) | Preparation method of 2-hydroxyisophthalic acid | |
| CN106279207A (en) | A kind of synthetic method of cefdinir | |
| CN104530112A (en) | Method for preparing everolimus intermediate and ethylated impurities thereof | |
| CN108299149A (en) | The synthetic method of high-purity O LED intermediate 1- bromine pyrenes | |
| CN105985309B (en) | Preparation method of high-purity lubiprostone compound | |
| CN113214123A (en) | Synthetic method of S-trityl-L-cysteine amide | |
| CN103787998B (en) | The synthetic method of a kind of bifunctional chelating agent p-SCN-NODA | |
| CN107235982B (en) | The synthetic method of 5 (6H) carboxylate of tert-butyl 7- hydroxyl -7,8- dihydro -4H- pyrazolo diazepine | |
| CN102260255B (en) | Simple and convenient synthesis method of 9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-3-isobutyl-2H-benzo[a] quinolizidine-2-ketone | |
| CN104926682A (en) | P-chlorophenylu hydrazine hydrochloride preparation method | |
| CN109651368A (en) | The preparation method of 4- methyl formate -2- oxygen -1,8- diaza spiro [4.5] decane -8- t-butyl formate | |
| CN110183368A (en) | The synthetic method of (3R, 4S) -1- fluorenylmethyloxycarbonyl -4- N-ethyl pyrrole N -3- carboxylic acid suitable for industrialization | |
| CN104744424B (en) | A kind of preparation method of ticagrelor midbody | |
| CN106995446B (en) | Preparation method of Bruton's tyrosine kinase inhibitor | |
| UA114158C2 (en) | A method for preparing an intermediate of iopromide | |
| CN102219744B (en) | Preparation method of telmisartan intermediate and intermediate compound | |
| CN105017251B (en) | A kind of Preparation Method And Their Intermediate of nk 1 receptor antagonist | |
| CN104109111B (en) | The preparation method of Tosi acid Bei Gelieting and its intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20160824 |