CN102167680B - Preparation method of octahydrocyclopenta[c]pyrrole carboxylic acid derivative - Google Patents
Preparation method of octahydrocyclopenta[c]pyrrole carboxylic acid derivative Download PDFInfo
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- CN102167680B CN102167680B CN201110070039.7A CN201110070039A CN102167680B CN 102167680 B CN102167680 B CN 102167680B CN 201110070039 A CN201110070039 A CN 201110070039A CN 102167680 B CN102167680 B CN 102167680B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- -1 octahydrocyclopenta[c]pyrrole carboxylic acid derivative Chemical class 0.000 title abstract description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 22
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims abstract description 16
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000002904 solvent Substances 0.000 claims abstract description 12
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229910052744 lithium Inorganic materials 0.000 claims abstract description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000013110 organic ligand Substances 0.000 claims abstract description 9
- 229910002092 carbon dioxide Inorganic materials 0.000 claims abstract description 7
- 239000001569 carbon dioxide Substances 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 33
- 150000003233 pyrroles Chemical class 0.000 claims description 19
- 238000006243 chemical reaction Methods 0.000 claims description 18
- WRHZVMBBRYBTKZ-UHFFFAOYSA-N pyrrole-2-carboxylic acid Chemical class OC(=O)C1=CC=CN1 WRHZVMBBRYBTKZ-UHFFFAOYSA-N 0.000 claims description 14
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical group [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 claims description 11
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 6
- PQLFROTZSIMBKR-UHFFFAOYSA-N ethenyl carbonochloridate Chemical compound ClC(=O)OC=C PQLFROTZSIMBKR-UHFFFAOYSA-N 0.000 claims description 6
- LLLMDRXIQZOTJE-UHFFFAOYSA-N 1,5-diazocine Chemical compound C1=CN=CC=CN=C1 LLLMDRXIQZOTJE-UHFFFAOYSA-N 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 4
- UZHVXJZEHGSWQV-UHFFFAOYSA-N 1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole Chemical compound C1NCC2CCCC21 UZHVXJZEHGSWQV-UHFFFAOYSA-N 0.000 abstract 1
- 239000007795 chemical reaction product Substances 0.000 abstract 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 208000005176 Hepatitis C Diseases 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000003814 drug Substances 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 201000007270 liver cancer Diseases 0.000 description 3
- 208000014018 liver neoplasm Diseases 0.000 description 3
- 229960000329 ribavirin Drugs 0.000 description 3
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 3
- 239000012266 salt solution Substances 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 241000711549 Hepacivirus C Species 0.000 description 2
- 102000014150 Interferons Human genes 0.000 description 2
- 108010050904 Interferons Proteins 0.000 description 2
- 101800001020 Non-structural protein 4A Proteins 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- 235000011089 carbon dioxide Nutrition 0.000 description 2
- 208000019425 cirrhosis of liver Diseases 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 208000010710 hepatitis C virus infection Diseases 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 229940079322 interferon Drugs 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 241000134307 Hepatitis C virus genotype 1 Species 0.000 description 1
- 102000012479 Serine Proteases Human genes 0.000 description 1
- 108010022999 Serine Proteases Proteins 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229960000846 camphor Drugs 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- BBAWEDCPNXPBQM-GDEBMMAJSA-N telaprevir Chemical compound N([C@H](C(=O)N[C@H](C(=O)N1C[C@@H]2CCC[C@@H]2[C@H]1C(=O)N[C@@H](CCC)C(=O)C(=O)NC1CC1)C(C)(C)C)C1CCCCC1)C(=O)C1=CN=CC=N1 BBAWEDCPNXPBQM-GDEBMMAJSA-N 0.000 description 1
- 229960002935 telaprevir Drugs 0.000 description 1
- 108010017101 telaprevir Proteins 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Pyrrole Compounds (AREA)
Abstract
The invention discloses a preparation method of an octahydrocyclopenta[c]pyrrole carboxylic acid derivative. The method comprises the following steps: octahydrocyclopenta[c]pyrrole protected by N is used as raw material, one of tetrahydrofuran, methyl tert-butyl ether and dioxane is used as solvent, chiral organic ligand is added to react with lithium alkylide for 2-3 hours at -50 DEG C to -78 DEG C, then the reaction product reacts with carbon dioxide or ethyl chloroformate to obtain the octahydrocyclopenta[c]pyrrole carboxylic acid derivative. The preparation method of the octahydrocyclopenta[c]pyrrole carboxylic acid derivative has short synthetic route and high yield and can be used to realize mass production successfully.
Description
Technical field
The present invention relates to a kind of preparation method of pharmaceutical intermediate, relate in particular to the also preparation method of [c] pyrrole carboxylic acid derivative of a kind of octahydro cyclopentyl.
Background technology
Hepatitis C (HCV) is viral since 1989 find, global PI toxicity hepatitis C patients approximately 1.7 hundred million, and year new cases 300～4,000,000, infect as main take hepatitis C virus 1 type, account for 70%.Hepatitis C is mainly by blood-borne, and the average infection rate in the whole world is 3%, Chinese infection rate approximately 3.2%, domestic antibody to hepatitis C positive approximately 4,000 ten thousand (1b, 2a).Hepatitis C easily transfers to chronic, and if do not treated, number turnover is up to 75%～85%.After hepatitis C infection 20～30 years, 10%～20% transfers liver cirrhosis to; Hepatitis C infection 30 years, 1～3% develops into liver cancer.According to statistics, global 27% liver cirrhosis and 25% liver cancer derive from hepatitis C.Liver cancer is occurred frequently in China, occupies second.
The Decision Resource company (Decision Resources) of the U.S. points out that in the research report of 2007 hepatitis C virus treatment market will increase nearly five times within Future Ten year, increases to more than 10,000,000,000 dollars in 2017 from approximately 2,000,000,000 dollars in 2007.As the China of developing country, due to the understanding deficiency to hepatitis C, much infect the case of hepatitis C out in the cold or treat as other hepatitis, along with the raising of medical level, its market potential demand is huge.The standard treatment of current treatment hepatitis C is polyoxyethylene glycol Interferon, rabbit and ribavirin (ribavirin) combination therapy, this therapy can be greater than 70% to HCV gene 2 types and 3 type infected patient curative ratios, but is only 40%～50% to HCV gene 1 type infected patient curative ratio.The treatment erious adverse reaction of polyoxyethylene glycol Interferon, rabbit and ribavirin, price is high, and patient tolerability is poor.
Current anti-hepatitis C drug research is very active, and the main pharmaceuticals in the whole world has oneself studies the project that suppresses hepatitis C.Research HCV virus replication necessary NS3/NS4A multifunctional protein enzyme (serine protease) inhibitor is at present nearest from market in the HCV medicine that carries out clinical trial.NS3/NS4A proteinase inhibitor of greatest concern surely belongs to the VX950(Telaprevir of Vertex company development at present).VX950 has now entered III clinical trial phase.VX950 very likely becomes first inhibition hepatitis C virus small molecules medicine of U.S. FDA approval.VX950 complex structure, it,, containing five chiral centres, is made up of 4 alpha-non-natural amino acids.Its key intermediate, there is the problems such as route is long, yield is low in octahydro cyclopentyl also [c] pyrroles-2-carboxylic acid synthetic, brings difficulty to scale operation.
Summary of the invention
The technical problem to be solved in the present invention is to provide the also preparation method of [c] pyrrole carboxylic acid derivative of a kind of octahydro cyclopentyl, and the method synthetic route is short, yield is high, and scale operation can be realized smoothly.
In order to solve the problems of the technologies described above; octahydro cyclopentyl of the present invention is the preparation method of [c] pyrrole carboxylic acid derivative also; comprise step: the octahydro cyclopentyl of the N protection representing take following structural formula I also [c] pyrroles is raw material; take the one in tetrahydrofuran (THF), methyl tertiary butyl ether or dioxane as solvent; add chirality organic ligand; at-50 ℃～-78 ℃; with lithium alkylide reaction 2～3 hours; again with carbon dioxide or Vinyl chloroformate reaction; obtain also [c] pyrrole carboxylic acid derivative of the octahydro cyclopentyl shown in following structural formula II, its reaction formula is as follows:
Preferably, described octahydro cyclopentyl also [c] pyrroles's N protecting group P is tertbutyloxycarbonyl, and N-tertbutyloxycarbonyl octahydro cyclopentyl also [c] pyrroles's (III) structural formula is as follows:
Preferably, described chirality organic ligand comprises (+) Tocosamine or (+)-3-methyl-ten dihydro-1,5-methylene-pyridine-[1,2-a] [1,5] diazocine.
Preferably; take the octahydro cyclopentyl of N protection also [c] pyrroles as raw material; take the one in tetrahydrofuran (THF), methyl tertiary butyl ether or dioxane as solvent; add chirality organic ligand; at-78 ℃; with lithium alkylide reaction 2～3 hours, then react with carbon dioxide or Vinyl chloroformate, obtain also [c] pyrrole carboxylic acid derivative of octahydro cyclopentyl.
Preferably, described lithium alkylide is s-butyl lithium; Preferred, described lithium alkylide is the cyclohexane solution containing s-butyl lithium.
Preferably, described solvent is methyl tertiary butyl ether.
Octahydro cyclopentyl of the present invention is the preparation method of [c] pyrrole carboxylic acid derivative also, and synthetic route is short, yield is high, and scale operation can be realized smoothly.
Embodiment
The invention provides the also preparation method of [c] pyrrole carboxylic acid derivative of a kind of octahydro cyclopentyl.Octahydro cyclopentyl also [c] pyrrole carboxylic acid derivative is the important intermediate of preparation VX950 and other medicines; its chemical structural formula is as shown in the formula (V); R1 is wherein the one of alkoxyl group, hydroxyl or Chiral Amine; R2, R3 are the one in hydrogen, fluorine, hydroxyl, and N protecting group (P) is tertbutyloxycarbonyl, carbobenzoxy-(Cbz) or chirality carbalkoxy.This compound is optical purity.Preparation method of the present invention is from also [c] pyrroles of octahydro cyclopentyl of N protection, and low temperature is through highly basic dehydrogenation, under chiral environment, and electrophilic group reaction, introduce chirality carboxyls at 2, obtain also [c] pyrrole carboxylic acid derivative of octahydro cyclopentyl.
The inventive method concrete steps comprise: the octahydro cyclopentyl of the N protection representing take following structural formula I also [c] pyrroles is raw material; take the one in tetrahydrofuran (THF), methyl tertiary butyl ether or dioxane as solvent; add chirality organic ligand; at-50 ℃～-78 ℃; with lithium alkylide reaction 2～3 hours; with carbon dioxide or Vinyl chloroformate reaction, obtain also [c] pyrrole carboxylic acid derivative of the octahydro cyclopentyl shown in following structural formula II again, its reaction formula is as follows:
The inventive method synthetic route is short, yield is high.The key intermediate chirality octahydro cyclopentyl of VX950 also [c] pyrroles-2-carboxylic acid (IV) can be directly from the octahydro cyclopentyl of the whirlpool that disappears also [c] pyrroles (I) step obtain.In a preferred embodiment of the invention; the octahydro cyclopentyl of employing N-tertbutyloxycarbonyl (N-Boc) protection also [c] pyrroles (III) is raw material; using (+)-Tocosamine as chirality organic ligand; after the reaction of-78 ℃ and s-butyl lithium (s-BuLi); then with carbon dioxide reaction; obtain also [c] pyrroles-2-carboxylic acid (IV, the wherein R of octahydro cyclopentyl of chirality
1=OH), its reaction formula is as follows:
Below by embodiment, the present invention is further detailed explanation.
embodiment 1
N-Boc octahydro cyclopentyl is [c] pyrroles III (0.42 g also, 2 mmol) and (+)-Tocosamine (0.56 g) is dissolved in (20 mL) in methyl tertiary butyl ether, be cooled to-78 ℃ with dry ice-propanone cryostat, be added dropwise to s-butyl lithium (containing the cyclohexane solution of 1.4 M s-butyl lithium, 2.1 mL).Stir after 3 hours at-78 ℃, pass into dry carbonic acid gas (0.5 hour).Reaction is raised to room temperature gradually, and stirring is spent the night.Be cooled to 0-5 ℃, add HCl (1N), adjust pH to 2-3, extract 2 times by ethyl acetate, merge organic layer, after the each washing of water and salt solution 2 times, anhydrous sodium sulfate drying, filters, after evaporated under reduced pressure solvent, residue through silica gel column chromatography separate, obtain N-tertbutyloxycarbonyl octahydro cyclopentyl also [c] pyrroles-2-carboxylic acid IV (0.33 g).
embodiment 2
N-Boc octahydro cyclopentyl is [c] pyrroles III (4.2 g, 20 mmol) and (+)-3-methyl-ten dihydro-1 also, 5-methylene-pyridine-[1,2-a] [1,5] diazocine (4.07 g, 21 mmol) is dissolved in (150 mL) in methyl tertiary butyl ether, is cooled to-78 with dry ice-propanone cryostat
oc, is added dropwise to s-butyl lithium (cyclohexane solution of 1.4 M, 15 mL, 21 mmol).-78
oc stirred cryostat after 3 hours, passed into dry carbonic acid gas (0.5 hour).Reaction is raised to room temperature gradually, and stirring is spent the night.Be cooled to 0-5
oc, adds HCl (1N), adjusts pH to 2-3, extracts (2 x 200 mL) by ethyl acetate, merges organic layer.After the each washing of organic layer water and salt solution 2 times, anhydrous sodium sulfate drying, filters, and after evaporated under reduced pressure solvent, residue separates through silica gel column chromatography, obtain chirality N-tertbutyloxycarbonyl octahydro cyclopentyl also [c] pyrroles-2-carboxylic acid IV (2.9 g).
embodiment 3
N-Boc octahydro cyclopentyl is [c] pyrroles III (1.39 g, 6.6 mmol) and (+)-3-methyl-ten dihydro-1 also, 5-methylene-pyridine-[1,2-a] [1,5] diazocine (1.54 g, 7.92 mmol) is dissolved in (20 mL) in ether, is cooled to-50 with dry ice-propanone cryostat
oc, is added dropwise to s-butyl lithium (cyclohexane solution of 1.4 M, 5.66 mL, 7.92 mmol).-50
oc stirred cryostat after 2 hours, added ether (10 mL) solution of Vinyl chloroformate (1.25 mL, 13.2 mmol).Reaction is raised to room temperature gradually, and stirring is spent the night.Be cooled to 0-5
oc, adds HCl (1 N), adjusts pH to 5-6, extracts (2 x 50 mL) by ethyl acetate, merges organic layer.After the each washing of organic layer water and salt solution, anhydrous sodium sulfate drying, filters, after evaporated under reduced pressure solvent, through silica gel column chromatography separate (10% ethyl acetate and normal hexane), obtain chirality N-tertbutyloxycarbonyl octahydro cyclopentyl also [c] pyrroles-2-carboxylic acid, ethyl ester (0.62 g)
The above embodiment has only expressed embodiments of the present invention, and it describes comparatively concrete and detailed, but can not therefore be interpreted as the restriction to the scope of the claims of the present invention.It should be pointed out that for the person of ordinary skill of the art, without departing from the inventive concept of the premise, can also make some distortion and improvement, these all belong to protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be as the criterion with claims.
Claims (7)
1. the also preparation method of [c] pyrrole carboxylic acid derivative of octahydro cyclopentyl; it is characterized in that; comprise step: the octahydro cyclopentyl of the N protection representing take following structural formula I also [c] pyrroles is raw material; take the one in tetrahydrofuran (THF), methyl tertiary butyl ether or dioxane as solvent; add chirality organic ligand; at-50 ℃～-78 ℃; with lithium alkylide reaction 2～3 hours; again with carbon dioxide or Vinyl chloroformate reaction; obtain also [c] pyrrole carboxylic acid derivative of the octahydro cyclopentyl shown in following structural formula II, its reaction formula is as follows:
Wherein, P is tertbutyloxycarbonyl; R
1for alkoxyl group or hydroxyl; Described chirality organic ligand comprises (+) Tocosamine or (+)-3-methyl-ten dihydro-1,5-methylene-pyridine-[1,2-a] [1,5] diazocine.
2. preparation method according to claim 1; it is characterized in that; take the octahydro cyclopentyl of N protection also [c] pyrroles as raw material; take the one in tetrahydrofuran (THF), methyl tertiary butyl ether or dioxane as solvent; add chirality organic ligand, at-78 ℃, and lithium alkylide reacts 2～3 hours; with carbon dioxide or Vinyl chloroformate reaction, obtain also [c] pyrrole carboxylic acid derivative of octahydro cyclopentyl again.
3. preparation method according to claim 1, is characterized in that, described lithium alkylide is s-butyl lithium.
4. preparation method according to claim 3, is characterized in that, described lithium alkylide is the cyclohexane solution containing s-butyl lithium.
5. preparation method according to claim 2, is characterized in that, described lithium alkylide is the cyclohexane solution containing s-butyl lithium.
6. preparation method according to claim 1, is characterized in that, described solvent is methyl tertiary butyl ether.
7. preparation method according to claim 5, is characterized in that, described solvent is methyl tertiary butyl ether.
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| US10300050B2 (en) | 2016-02-05 | 2019-05-28 | Achieve Pharma Uk Limited | Succinate salt of cytisine and use thereof |
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