CN1177956A - Process for preparing prostaglandin E1, E2 and analogs thereof using furylcopper reagents - Google Patents

Process for preparing prostaglandin E1, E2 and analogs thereof using furylcopper reagents Download PDF

Info

Publication number
CN1177956A
CN1177956A CN 96192427 CN96192427A CN1177956A CN 1177956 A CN1177956 A CN 1177956A CN 96192427 CN96192427 CN 96192427 CN 96192427 A CN96192427 A CN 96192427A CN 1177956 A CN1177956 A CN 1177956A
Authority
CN
China
Prior art keywords
reagent
alkyl group
lithium
low alkyl
iii
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
Application number
CN 96192427
Other languages
Chinese (zh)
Inventor
M·特玻特
B·泽克
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Vivus LLC
Original Assignee
Vivus LLC
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Vivus LLC filed Critical Vivus LLC
Priority to CN 96192427 priority Critical patent/CN1177956A/en
Publication of CN1177956A publication Critical patent/CN1177956A/en
Pending legal-status Critical Current

Links

Landscapes

  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

A process for synthesizing prostaglandin E1, E2 and derivatives thereof is provided. The process is a 'one-pot' method in which 2-furyllithium, copper cyanide, a lower alkyllithium reagent and either an (E)-alkenylstannane or a halogenide are combined with cyclopentenone(II) in which A, R6 and R7 are as defined herein. The reaction gives rise to the desired prostaglandin product in yields of 80% or higher.

Description

Prepare PGE with the furyl Tong Shiji 1, E 2And the method for analogue
Technical field
The present invention relates to the synthetic method of prostanoic acid derivative, specifically, relate to and use the furyl Tong Shiji by " one pot " method synthesis of prostaglandins E 1(" PGE 1"), PGE 2(" PGE 2") and derivative.
Background technology
Prostaglandin(PG) is the bioactive class resin acid of a class, has the common trait of prostate gland alkane-1-acid (prostan-1-oic acid) structure:
There to be or not exist some functional group on the pentamethylene ring is foundation, prostaglandin(PG) can be divided into E, F, A, B, C and D type.Index number is (as prostaglandin(PG) " E 1" and prostaglandin(PG) " E 2" in index number) be meant the quantity of unsaturated link(age) in side chain; Subscript " α " or " β " are (as prostaglandin(PG) " F 1 α" or prostaglandin(PG) " F 1 β") be meant the configuration of substitution in ring base.
The biological activity of prostaglandin(PG) comprises the stimulation unstriated muscle, the arteriole expansion, and bronchiectasis brings high blood pressure down, and suppresses stomachial secretion, lipolysis and platelet aggregation, brings out production, miscarriage and menstruation and increase intraocular pressure.PGE 1Especially a kind of well-known bronchodilator and vasodilator are known that also it can stimulate kidney cortex to discharge erythropoietin and are suppressed anaphylaxis and thrombocyte condenses.PGE 2Be the Mammals prostaglandin(PG) of the most common and tool biopotency, be used for uterus muscle and shrink, gastric acid inhibitory secretion, protection stomach mucous membrane inwall, it and PGE 1The same, discharge stimulant as bronchodilator and kidney cortex erythropoietin.The existing summary widely of the performance of various prostaglandin(PG)s; For example, can be referring to the article of people such as Ramwell in nature (Nature) 221:1251 (1969).
Can pass through the enzymatic conversion biosynthesizing prostaglandin(PG) of the unsaturated fatty acids of 20 carbon atoms.For example, bridge superoxide PGG 2And PGH 2Can act on lipoid precursor eicosatetraenoic acid by prostaglandin(PG) epoxidase mixture and make, and PGE 1Be by 8,11,14-eicosatrienoic acid enzymatic conversion and biosynthetic.The biosynthetic Review Study of prostaglandin(PG) is at the Prog.Biochem.Pharmacol.5:109 (1969) of Samuelsson.
Various prostaglandin(PG)s many synthesis paths have been explored.People such as Corey have developed and closed inferior thallium with cyclopentadiene is raw material, through synthetic PGE of 20 steps 2And PGF 2 αThis method has proved the prostaglandin(PG) that is applicable to a synthetic series.Two protection PGF 2 αCatalytic reduction alternative saturated 5, the two keys of 6-generate:
Figure A9619242700081
Transform subsequently, form PGE 1And PGF 1 αReferring to Corey etc., JACS.91:5675 (1969), Corey etc., JACS.92:2586 (1970) and Corey etc., tetrahedron communication (Tetrahedron Letters) 307 (1970).
Another kind of synthesis path uses norbornadiene as raw material, also has a kind of method to use racemize two ring [3,2,0] hept-2-ene"-6-ketone as raw material.A kind of synthetic method in back comprises that enantiomorph converges (enantioconvergent) method, so that use following two kinds of enantiomorphs, need not optical resolution.
But, still need a kind of simpler and more direct method to synthesize various prostaglandin(PG)s, especially PGE in the art 1, PGE 2And derivative.Also require this synthetic method that the product of requirement can be provided with higher relatively productive rate, and require this method simple, can directly amplify in proportion, and use reagent on sale on inexpensive, the market.The present invention relates to this method, comprise and use the synthetic PGE of lithium Tong Shiji " a pot " 1, PGE 2And analogue.
Association area
Except the publication that previous section is mentioned, also interested in following document, because they relate to the synthetic method of derivatives of prostaglandins.
The United States Patent (USP) 4 of Sih, 031,129 and 4,088,536 relate to cyclopentadiene close alkylation diene that the reaction of lithium and 7-bromine oil of cognac, oxidation so generate, from reaction mixture, reclaim 2-(6 '-carbonyl oxyethyl group hexyl)-4-hydroxycyclopent alkene-1-ketone, make it with the dihydropyrane reaction generate THP trtrahydropyranyl ether, at last the iodate tri-n-butyl phosphine close copper in the presence of make the trans octene reaction of this intermediate and 1-lithium-1-, generation racemize 15-deoxy prostaglandin E1 ethyl ester is to prepare the method for racemize 15-deoxy prostaglandin.
The United States Patent (USP) 4,149,007 of Buckler etc. is disclosed in the PGE that the C-14 position has phenyl substituent 1The synthetic method of derivative; This method comprises uses copper acid organolithium reagent so that be connected on the side chain of C-12 position, goes protection and hydrolysis with weak acid after the coupling.
The United States Patent (USP) 4,282,372 of Matsuo etc. has been described the method for preparing the cyclopentenol ketone derivatives, and this derivative allegedly is suitable for being particularly suitable for preparing prostaglandin(PG) as intermediate.Described method is included in and transforms the furans that replaces under the acidic conditions, perhaps makes it to react with chlorine or bromine in the presence of alkali and alcohol.
The United States Patent (USP) 4,360,688 of little Floyd is chiefly directed to the synthetic method of the derivatives of prostaglandins of one-S-of side joint aryl moiety in the extended side chain in C-8 position.Also disclose and make this compound reaction so that will have-ethylidene of S-aromatic yl group partly changes into the method for vinylidene group.
The United States Patent (USP) 4,452,994 of Hill etc. relates to and separate 11 from reaction mixture, 16-or 11, the method for 15-dihydroxyl prostaglandin(PG).This method comprises the use lithium halide.
The United States Patent (USP) 4 of little Floyd etc.; 474; 979,4; 644; 079,4; 983; 753 and 5,166,369 relate to a kind of synthetic method; comprise 4-hydroxyl with the cyclopentenyl part of for example trimethyl silyl or THP trtrahydropyranyl guard ring pentenoyl (cyclopentenoyl) compound; use copper acid lithium reagent (as copper acid lithium-1-pentyne) to convert it into prostaglandin(PG) (1-methyl isophthalic acid 6,16-dimethyl-11 α, 15 alpha-dihydroxy-s-9-ketone group (oxo)-2 of requirement subsequently; 13-is trans, trans prostadienoic acid ester).
What the United States Patent (USP) 4,535,180 of Grudzinskas etc. was claimed is the synthetic method of prostaglandin analogue.But all claimed compounds all have a methyl or a C 2-C 4Thiazolinyl directly be connected on the pentamethylene ring.
The United States Patent (USP) 4,543,421 of Corey etc. has been described side chain " R 1" be connected to the locational method of C-12 of prostaglandin analogue.This method comprises uses alkyl lithium reagents and cupric cyanide reaction to form cyanogen copper acid lithium; Make the cyclopentenone reaction of this compound and replacement subsequently, randomly be hydrolyzed subsequently.
The United States Patent (USP) 4,785,124,4,904,820 of Campbell etc. has been described and has been made cuprate title complex and stannane (as 1, the two three normal-butyl stannyl ethene of 2-) the senior cuprate title complex of prepared in reaction, uses this product to prepare the ω side chain of prostaglandin(PG) subsequently.
The United States Patent (USP) 4,952,710 of Babiak etc. has been described with senior copper acid title complex and chirality cyclopentenes prepared in reaction cyclopentenes 6-heptenoic acid derivative.
The United States Patent (USP) 5,055,604 of Babiak etc. relates to synthetic preparation derivatives of prostaglandins, comprises that (1) makes alkynes and chlorination zirconocene (zirconocene) hydride reaction preparation " E-thiazolinyl " zirconium compounds; (2) make the reaction of this product and cyanogen copper acid lithium reagent, generate cuprate title complex intermediate; And (3) make cuprate title complex intermediate and cyclopentenone reaction.
The United States Patent (USP) 5,191,109 of Minai etc. has been described the preparation method of optically active 4-hydroxycyclopent ketenes.This method is included in and makes half ester (VI) and furans reaction generate chaff ketone under the existence of trifluoroacetic anhydride, subsequently it is reduced into furfuryl alcohol.With pH is that the water-containing solvent of 3.5-6 is handled this furfuryl alcohol, generates 3-hydroxycyclopent ketenes or racemize 4-hydroxycyclopent ketenes, further handles it with aliphatic carboxylic acid subsequently, generates the product that requires.
Japan publication publication No.63-077837 has described the furan compound that will replace and has changed into the cyclopentenone compound.
Lipshutz has proposed to use the cuprate title complex to form new C-C from a series of synthetic angles in " application of the senior organic copper Barbiturates of blended in organic synthesis " synthetic 4:325-341 (1987).Formula RtRCu (CN) Li has especially been described 2And RtRCu (SCN) Li 2The preparation and the use of senior cuprate title complex." Rt " representative is transferred to the group that forms C-C on the organic compound, and wherein R represents residue.
The general introduction of invention
Therefore, main purpose of the present invention provide a kind of categorical, reaction of " a pot " with synthesis of prostaglandins (as PGE 1, PGE 2And derivative), be used for satisfying the above-mentioned needs of this area.
Another object of the present invention provides a kind of synthetic method, and it comprises cyclopentenone and the reaction of furyl Tong Shiji that makes suitable replacement.
Another object of the present invention provide a kind of by 2-furyl lithium, cupric cyanide (CuCN), low alkyl group lithium and (E)-reaction of alkenylstannane (perhaps halogenide) generates the synthetic method of furyl Tong Shiji.
A further object of the present invention provides and a kind ofly makes above-mentioned compound side by side, and non-stepwise ground reacts, and need not the synthetic method of distinguishing synthesis step and need not separation of intermediates and so on.
Those of skill in the art in the synthetic organic chemistry field can understand other purpose of the present invention easily by reading this specification sheets and claims.
The invention provides a kind of PGE 1, PGE 2And the synthetic method of derivative, all described prostaglandin(PG)s all can be represented by formula (I) structure:
Figure A9619242700101
In formula (I): R 1And R 2Can be identical or different, and be selected from following formula: R wherein 3And R 4Be selected from hydrogen, OR respectively 5And low alkyl group; A is selected from following formula:
Figure A9619242700112
R wherein 5Be selected from hydrogen, THP trtrahydropyranyl, tetrahydrofuran base, three low alkyl group silyls, 1-methyl isophthalic acid-methoxy ethyl, 1-methyl isophthalic acid-ethoxyethyl group and-(CO)-R 8, R wherein 8It is the low alkyl group that hydrogen, low alkyl group or halogen replace;
R 6Be ethylidene or vinylidene;
R 7Be R 5, low alkyl group or low-grade alkenyl.
Described method comprises the cyclopentenone that makes formula (II):
Figure A9619242700113
Wherein A, R 6And R 7As defined above, with the mixture reaction of 2-furyl lithium, cupric cyanide, low alkyl group lithium reagent and halogenide (III) (perhaps (E)-alkenylstannane (IV)):
(III) B-CH＝CH-R 1-R 2-R 10
(IV) M-CH＝CH-R 1-R 2-R 10
In compound (III), B is a halogenide, R 1And R 2As defined above.In compound (IV), M is-Sn (R 9) 3, R wherein 9It is low alkyl group.At compound (III) with the substituent R (IV) 10It is low alkyl group.
Detailed description of the present invention
Before detailed description the present invention, should be appreciated that except as otherwise noted the present invention is not subjected to the restriction of concrete reagent, reaction conditions etc., because this can change.Should also be appreciated that term as used herein only for the purpose of describing specific examples, the present invention is not limited.
Be noted that the singulative " " that is used for this specification sheets and appending claims, " a kind of " and " this " etc. comprise the content of plural number, unless should in have clear and definite qualification.Therefore, " a kind of cyclopentenone " comprises the mixture of cyclopentenone, and " a kind of alkyl lithium reagents " comprises the mixture of this reagent, or the like.
In this specification sheets and appending claims, limit a series of terms with following meanings:
Term " prostaglandin(PG) " is meant and has prostate gland alkane-compound of 1-acid skeleton in this article:
Figure A9619242700121
Using the prostaglandin(PG) of this synthetic method preparation is PGE 1, PGE 2And derivative, the compound that promptly has top formula (I) structure.
Term " alkyl " is meant the saturated hydrocarbyl with 1-24 carbon atom of side chain or non-side chain herein, as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, octyl group, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl etc.Term " low alkyl group " is meant to have 1-8, better has 1-6, preferably has the alkyl of 1-4 carbon atom.Term " junior alkyl halides " is meant to have a hydrogen atom at least, and 1-3 hydrogen atom arranged usually, but the low alkyl group with 1-6 carbon atom that preferably only has a hydrogen atom to be replaced by halogen atom.
Term " thiazolinyl " is meant side chain or the non-side chain hydrocarbon chain that contains 2-24 carbon atom and have two keys at least." low-grade alkenyl " is meant to have 2-8, better have 2-6, preferably has the thiazolinyl of 2-4 carbon atom.Term " halo low-grade alkenyl " is meant that at least one hydrogen atom is by low-grade alkenyl that halogen atom replaced.
Term " alkoxyl group " is meant the alkyl that connects by single terminal ehter bond herein; " alkoxyl group " can be defined as-OR, wherein R is an alkyl defined above." lower alkoxy " is meant and contains 1-8, better contain 1-6, preferably contains the alkoxyl group of 1-4 carbon atom.
" halogen ", " halogen " or " halogenide " are meant fluorine, chlorine, bromine or iodine, typically refer to the hydrogen atom in the halogen substituted organic compound, and in halogen, chlorine is best.
" choose wantonly " or " randomly " is meant that subsequently situation about describing can take place or can not take place, this description comprises the situation that situation that described situation takes place and described situation do not take place.For example, phrase " optional covalent linkage " is meant that a covalent linkage can exist or can not exist, and this description comprises situation and the non-existent situation of covalent linkage that covalent linkage exists.
As mentioned above, the compound that has formula (I) structure:
Figure A9619242700131
Wherein A, R 1, R 2, R 6And R 7As defined above, can be by the cyclopentenone (II) that replaces
Figure A9619242700132
Make with 2-furyl lithium, cupric cyanide, low alkyl group lithium reagent and halogenide (III) (or (E)-alkenylstannane (IV)) reaction.Be preferably, the mole number of the four kinds of reagent in back does not have tangible production loss although generally can hold up to the relative quantity variation of 10-20 mole % about equally.This reaction is to carry out in appropriate organic solvent (preferably nonpolar, aprotonic solvent are as tetrahydrofuran (THF) (THF) or ether), and temperature of reaction is about-50～50 ℃, preferably is about-30～30 ℃.Reaction should be carried out under inert conditions (promptly in exsiccant nitrogen or argon atmospher), and the reaction times was at least 30 minutes approximately.
During beginning, preferably earlier 2-furyl lithium (being made by furans that roughly waits mole number and alkyl lithium reagents blending under about 10 ℃ or lower temperature) and cupric cyanide, low alkyl group lithium and compound (III) (perhaps compound (IV)) were mixed in the past adding cyclopentenone.The blending of furans, alkyl lithium reagents and cupric cyanide generates reagent (V):
Figure A9619242700133
To the long period, common can stablizing reached at least about 6 months this compound 0 ℃ of energy stable phase.Add compound (III) or (IV), a step ground is with about 0.3 subsequently: 1-1: 1 mol ratio (that is to say, if the amount that furans, lithium alkylide and compound (III) (perhaps compound (IV)) exist is about 1 mole respectively, then add 0.3-1 mole cyclopentenone) in this reaction mixture, add cyclopentenone (II), generate the derivatives of prostaglandins that requires.
Use alkali, for example ammonium hydroxide and so on stops this reaction.Isolate (as using dried over mgso) of organic substance and drying; With for example dilute hydrochloric acid product is gone protection subsequently,, separate as chromatography, crystallization or similar technology with conventional method.
With regard to employed concrete reagent, those of skill in the art in the synthetic organic chemistry field will recognize, if necessary, can (for example replace disclosed reagent by the identical reagent of use official energy, can use chlorination or bromination 2-furyl magnesium to replace 2-furyl lithium), and can use various low alkyl group lithium reagents, as lithium methide, lithium ethide, sec.-propyl lithium, n-propyl lithium etc.
Halid preferably example with formula (III) structure includes, but are not limited to:
Figure A9619242700141
Suitable (E)-alkenylstannane includes, but are not limited to:
Figure A9619242700151
Be also pointed out that if use the halogenide (III) of pure enantiomerism form or (E)-alkenylstannane (IV) product that makes so also is pure enantiomerism form.This experimental section below illustrates.
The technology that all raw materials that use in the present invention is synthetic and reagent all are commercially available or available routine is easily synthetic to be made.For example, alkyl lithium reagents, furans and cupric cyanide can obtain by multiple commercially available channel, and formula (II) racemize cyclopentenone can make in the described method of pharmaceutical chemistry magazine .20:1152 (1970) according to Collins etc., pure enantiotopic formula (II) cyclopentenone can be according to Pappo etc. at Tet.Lett., 1973, p.943 the method described in makes, the halogenide of formula (III) can be according to Jung etc. at Tet.Lett., 1982, p.3851, Weis etc. are at organic chemistry magazine 1979, p.1438 or Collins etc. at the pharmaceutical chemistry magazine, 1977, p.1152 the method described in makes, and formula (IV) alkenylstannane can be synthetic in the method described in the organic chemistry magazine 43:3450 (1978) according to Chen etc.
The advantage of the inventive method is that it has high isolated yield (being higher than 80-90% as a rule), and has good repeatability.Present method is amplified in proportion easily and can be made hundreds of gram prostaglandin(PG)s in " one pot " operation.Can use routine techniques (as crystallization or chromatography) easily to separate byproduct, and can obtain highly purified prostaglandin(PG) product.From the viewpoint of making, its advantage is that reagent mixture is stable, and (about 6 months or longer) store and do not have a tangible decomposition for a long time if desired.Employed whole chemical all is inexpensive and can commercially availablely buys.
The following example is used for intactly showing and illustrate how to implement synthetic method of the present invention to those skilled in the art, is not that the invention scope that the contriver thinks is limited.Made effort although just guarantee the precision of used numeral (as consumption, temperature etc.), some testing error and deviation allow.Except as otherwise noted, otherwise part is meant that weight part, temperature are meant degree centigrade, and pressure is or near normal pressure.
Experiment
All organometallic reactions all use anhydrous solvent to carry out in exsiccant nitrogen or argon atmospher.With reaction flask heat gun drying, all shift by sleeve pipe air sensitive reaction reagent before adding raw material or reagent.With 1H and 13C NMR (use Jeol 270 MHz spectrographs), infrared spectra (using Mattson Galaxy 5020 serial Fourier transform spectrometer,s), vapor-phase chromatography (using 5890GC/MS system of Hewlett-Packard) and HPLC (using the 1050LC of Hewlett-Packard) and if obtain authority's standard, also by relatively so that product is confirmed.
Embodiment 1
The original position of cyaniding (E)-thiazolinyl-2-furyl copper lithium-complex forms and is converted into Misoprostol (misoprostol):
To (2.6g, 28.9mmo1) (THF 35ml), adds 2-furyl lithium (1 equivalent) solution at 0 ℃ to middle adding anhydrous tetrahydro furan subsequently at the cupric cyanide in heat gun exsiccant 250ml three-necked round bottom flask.By overlapping effective lithium methide (1 equivalent) and R, S-stannane 1 (1.5 equivalent) (according to synthetic the obtaining of method of above-mentioned Chen etc.) is handled the solution that obtains.
Figure A9619242700161
In envrionment temperature the homogeneous phase solution that generates was stirred 3 hours, be cooled to the R of-65 ℃ and a collection of addings protection, S-ketenes 2 (7g, 19.8mmol) (according to synthetic the making of method of above-mentioned Collins etc.) solution in THF (35ml).Observe temperature and rise to-35 ℃ approximately.
Figure A9619242700171
-30～approximately-40 ℃ this homogeneous reaction mixture stirred 30 minutes and with ammonium chloride saturated aqueous solution (500ml contains the dense ammonium hydroxide of 50ml) and ethyl acetate (150ml) termination reaction.Isolate organic substance; evaporate it in a vacuum with dried over mgso and at about 45-55 ℃; obtain R; S-13E; 11-triethyl-silicane Oxy-1 6-trimethylsiloxy-16-methyl-9-ketone group prostatitis-13-alkene-1-acid methyl esters crude product; use the solution (30 minute) of 3M HCl in acetone that it is gone protection subsequently, obtain the Misoprostol crude product of light yellow oily.Mixed solution with hexane and methyl tertiary butyl ether is used the chromatography purification Misoprostol as gradient eluent on silica gel, obtain the pure Misoprostol 3 of 6.95g (92%) colorless oil. 1H NMR (CDCl 3, ppm): 3.63 (s, OCH 3), 2.64 and 2.74 (dd, C-10), 5.50 (m, C-12,14).
Embodiment 2
The original position of cyaniding (E)-thiazolinyl-2-furyl copper lithium-complex forms and transforms (using n-Butyl Lithium) is Misoprostol:
Repeat the step of embodiment 1, (18ml, 29mmol) solution in is isolated product 6.8g (90%) to replace lithium methide at hexane but be to use the 1.6M n-Butyl Lithium.
Embodiment 3
The original position of cyaniding (E)-thiazolinyl-2-furyl copper lithium-complex forms and is converted into PGE 1:
Repeat the step of embodiment 1, but use the solution of 18.6g (35mmol) S-stannane 4 (making) in THF (35ml) to replace reagent 1 according to described methods such as front Chen are synthetic,
And use the solution of 9.5g (21mmol) R-ketenes 5 (making) in THF (35ml) to replace R, S-ketenes 3 according to described methods such as front Pappo are synthetic
Figure A9619242700182
Go protection (2M HCl-acetone 1: 1,30 minutes room temperatures) and with obtaining PGE behind the chromatography purification 1(6.3g, 85%). 1H NMR (CDCl 3, ppm): 2.61 and 2.65 (dd, and 10-C) 0.90 (t, C-20).
Figure A9619242700183
PGE 1
Embodiment 4
The original position of cyaniding (E)-thiazolinyl-2-furyl copper lithium-complex forms and is converted into PGE 2:
Use is same as the method for embodiment 1, but is to use S-stannane 6 (making according to described methods such as front Chen are synthetic) to replace R, S-stannane 1.
(wherein, " THP " represents THP trtrahydropyranyl), and replace R, S-ketenes 2 with R-ketenes 7 (making) according to described methods such as front Pappo are synthetic.
Go protection (2M HCl-acetone 1: 1,15 minutes in room temperature) and, obtain PGE with behind the chromatography purification 2(80%). PGE 2
Embodiment 5
The original position of cyaniding (E)-thiazolinyl-2-furyl copper lithium-complex forms and is converted into PGE 1Methyl esters:
Repeat the method for embodiment 1, but be to use the solution of S-stannane 8 (17g, 35mmol make according to described methods such as front Chen are synthetic) in THF (35ml) to replace S-stannane 1:
And with the solution of R-ketenes 9 (6.55g, 21mmol make according to described methods such as front Pappo are synthetic) in THF (35ml)
Figure A9619242700202
Replace R-ketenes 2.Obtain PGE 1Methyl esters (6.6g, 85%). PGE 1Methyl esters
Embodiment 6
The original position of cyaniding (E)-thiazolinyl-2-furyl copper lithium forms and is converted into PGE 1:
(2.6g, 28.9mmol) the middle THF (35ml) that adds add the solution (0 ℃ hexane solution reaction with furans and n-Butyl Lithium make) of 2-furyl lithium in THF at 0 ℃ subsequently to the cupric cyanide in the 250ml three-necked flask.The solution that generates is cooled to is lower than-65 ℃, add (E)-thiazolinyl lithium (S-(E)-iodine alkene 10 or S-stannane 11 being made with the n-Butyl Lithium reaction in 1 hour) at-70 ℃ by sleeve pipe.The amber mixture that generates is stirred 30 minutes (60 ℃) and adds R-ketenes 12 (9.54g, 21mmol) solution in THF (40ml).
Figure A9619242700211
At-50 ℃ the homogeneous mixture was stirred 30 minutes, add ammonium chloride/ammonium hydroxide (10%) saturated aqueous solution (500ml) immediately, continue to stir 1 hour in envrionment temperature subsequently.Separate organic layer, with salt water washing secondary, dry and evaporation.Make it and the solution reaction of 500mg tosic acid pyridine in 150ml acetone and 30ml water 5 hours, go protection to obtain PGE 1Crude product.As elutriant this product of purifying on silica gel column chromatography, and crystallization in ether obtained 6.6g (89%) product with ethyl acetate-hexanes of 2: 1.

Claims (17)

1. the preparation method of a formula (I) prostaglandin(PG), Wherein: R 1And R 2Can be identical or different, and be selected from following formula:
Figure A9619242700022
R wherein 3And R 4Be selected from hydrogen, OR respectively 5And low alkyl group; A is selected from following formula:
Figure A9619242700023
R wherein 5Be selected from hydrogen, THP trtrahydropyranyl, tetrahydrofuran base, three low alkyl group silyls, 1-methyl isophthalic acid-methoxy ethyl, 1-methyl isophthalic acid-ethoxyethyl group and-(CO)-R 8, wherein
R 8Be the low alkyl group that hydrogen, low alkyl group or halogen replace,
R 6Be ethylidene or vinylidene,
R 7Be R 5, low alkyl group or low-grade alkenyl,
Described method comprises:
(a) preparation contains the reaction mixture of following component: first reagent that (i) is selected from 2-furyl lithium, chlorination 2-furyl magnesium and bromination 2-furyl magnesium, second reagent that (ii) comprises the low alkyl group lithium compound, (iii) comprise the 3rd reagent of cupric cyanide, and the 4th reagent that (iv) comprises halogenide (III) or (E)-alkenylstannane (IV):
(III) B-CH＝CH-R 1-R 2-R 10
(IV) M-CH＝CH-R 1-R 2-R 10
Wherein, B is a halogenide, and M is-Sn (R 9) 3, R wherein 9Be low alkyl group, R 10Be low alkyl group, R 1And R 2As defined above;
(b) make cyclopentenone (II) under the condition of one or more structural formulas (I) product being enough to form:
Figure A9619242700031
Contact with described reaction mixture.
2. the method for claim 1 is characterized in that first reagent is 2-furyl lithium.
3. method as claimed in claim 2 is characterized in that second reagent is selected from lithium methide, lithium ethide, n-propyl lithium, sec.-propyl lithium, n-Butyl Lithium, isobutyl-lithium and tert-butyl lithium.
4. the method for claim 1 is characterized in that the 4th reagent has the structure of formula (III).
5. method as claimed in claim 2 is characterized in that the 4th reagent has the structure of formula (III).
6. method as claimed in claim 5 is characterized in that the 4th reagent is selected from:
7. the method for claim 1 is characterized in that the 4th reagent has the structure of formula (IV).
8. method as claimed in claim 2 is characterized in that the 4th reagent has the structure of formula (IV).
9. method as claimed in claim 8 is characterized in that the 4th reagent is selected from:
Figure A9619242700042
10. the method for claim 1 is characterized in that the existing amount of the first, second, third and the 4th reagent is roughly equimolar in reaction mixture.
11. the method for claim 1 is characterized in that any one the mol ratio in cyclopentenone (II) and the first, second, third or the 4th reagent is about 0.3: 1-1: 1.
12. the method for claim 1 is characterized in that obstructed what intermediate of too leaving one's post has just obtained product.
13. the method for claim 1 is characterized in that step (b) in nonpolar, aprotonic solvent, is being about in-50～50 ℃ the temperature of reaction to carry out at least about 30 minutes.
14. method as claimed in claim 10 is characterized in that step (b) in nonpolar, aprotonic solvent, is being about in-50～50 ℃ the temperature of reaction to carry out at least about 30 minutes.
15. the method for claim 1 is characterized in that this method comprises that also (c) uses alkali termination reaction step (b).
16. method as claimed in claim 15 is characterized in that this method comprises that also (d) goes to protect with the product of diluted acid with step (c), and (e) uses chromatography or crystallization process separated product (I).
17. the preparation method of a formula (I) prostaglandin(PG),
Figure A9619242700051
Wherein: R 1And R 2Can be identical or different, and be selected from following formula:
Figure A9619242700052
R wherein 2And R 4Be selected from hydrogen, OR respectively 5And low alkyl group,
A is selected from following formula: R wherein 5Be selected from hydrogen, THP trtrahydropyranyl, tetrahydrofuran base, three low alkyl group silyls, 1-methyl isophthalic acid-methoxy ethyl, 1-methyl isophthalic acid-ethoxyethyl group and-(CO)-R 8, R wherein 8Be hydrogen, low alkyl group or halogenated low alkyl group,
R 6Be ethylidene or vinylidene,
R 7Be R 5, low alkyl group or low-grade alkenyl,
Described method comprises:
(a) preparation contains the roughly reaction mixture of the following component of equimolar amount: (i) 2-furyl lithium, and (ii) low alkyl group lithium compound, (iii) cupric cyanide, and (iv) halogenide (III) or (E)-alkenylstannane (IV):
(III) B-CH＝CH-R 1-R 2-R 10
(IV) M-CH＝CH-R 1-R 2-R 10
Wherein, B is a halogenide, and M is-Sn (R 9) 3, R wherein 9Be low alkyl group, R 1And R 2As defined above;
(b) in nonpolar, aprotonic solvent, under-50～50 ℃ of temperature of reaction approximately, make cyclopentenone (II):
Figure A9619242700061
At least reacted about 30 minutes with described reaction mixture, be regardless of what intermediate of leaving one's post;
(c) with alkali termination reaction step (b);
(d) go to protect with the product of diluted acid with step (c);
(e) use chromatography or crystallization process separated product (I).
CN 96192427 1995-03-10 1996-03-07 Process for preparing prostaglandin E1, E2 and analogs thereof using furylcopper reagents Pending CN1177956A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN 96192427 CN1177956A (en) 1995-03-10 1996-03-07 Process for preparing prostaglandin E1, E2 and analogs thereof using furylcopper reagents

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US08/403,251 1995-03-10
CN 96192427 CN1177956A (en) 1995-03-10 1996-03-07 Process for preparing prostaglandin E1, E2 and analogs thereof using furylcopper reagents

Publications (1)

Publication Number Publication Date
CN1177956A true CN1177956A (en) 1998-04-01

Family

ID=5128267

Family Applications (1)

Application Number Title Priority Date Filing Date
CN 96192427 Pending CN1177956A (en) 1995-03-10 1996-03-07 Process for preparing prostaglandin E1, E2 and analogs thereof using furylcopper reagents

Country Status (1)

Country Link
CN (1) CN1177956A (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102056887A (en) * 2008-04-09 2011-05-11 台湾神隆股份有限公司 Process for the preparation of prostaglandin analogues and intermediates thereof

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102056887A (en) * 2008-04-09 2011-05-11 台湾神隆股份有限公司 Process for the preparation of prostaglandin analogues and intermediates thereof
CN102056887B (en) * 2008-04-09 2014-03-19 台湾神隆股份有限公司 Process for the preparation of prostaglandin analogues and intermediates thereof

Similar Documents

Publication Publication Date Title
US4446147A (en) Azaprostacyclins, their preparation and pharmaceutical use
DE2659215A1 (en) PROSTAGLANDIN ANALOGA
GB2099814A (en) 15-deoxy-16-hydroxy prostaglandins
CN1263726C (en) Process and intermediates to prepare latanoprost
DE2704933A1 (en) PROSTAGLANDIN ANALOGS WITH TRIPLE BONDING BETWEEN C-13 AND C-14 AND THE METHOD OF MANUFACTURING IT
IL43589A (en) 16-phenoxy-15-hydroxy derivatives of 17,18,19,20-tetranorprostaglandins and their preparation
CN86108472A (en) 5-(2, the 5-dimethyl phenoxy)-2,2-dimethyl valeric acid preparation method's improvement
CN1177956A (en) Process for preparing prostaglandin E1, E2 and analogs thereof using furylcopper reagents
DE2659217A1 (en) PROSTAGLANDIN ANALOGA
AU696027B2 (en) Process for preparing prostaglandin E1, E2 and analogs thereof using furylcopper reagents
US6437152B1 (en) Intermediate for the synthesis of prostaglandins
US6310257B2 (en) Substituted cyclopentene derivatives and method for preparing the same
DE2704960A1 (en) PROSTAGLANDIN ANALOGS WITH TRIPLE BONDING BETWEEN C-13 AND C-14 AND THE METHOD OF MANUFACTURING IT
CN1023482C (en) Thiophen compouns and their preparation
CN1269783A (en) Process for making epoxide intermediates
US4260805A (en) 1-Descarboxy-1-ketoester (ketoacid)-prostaglandins
US4250321A (en) 1-Descarboxy-1-ketoester(ketoacid)-protaglandins
US4254275A (en) 1-Descarboxy-1-ketoester (ketoacid)-prostaglandins
DE2813305A1 (en) PROSTAGLANDINS AND METHOD OF MANUFACTURING THEREOF
US4250323A (en) 1-Descarboxy-1-ketoester(ketoacid)-prostaglandins
US4061672A (en) Derivatives of 9-hydroxy-13-trans-prostenoic acid
US4283550A (en) 1-Descarboxy-1-ketoester(ketoacid)-prostaglandins
IL45171A (en) 11-substituted-11-desoxy-pge2 analogues
DE2704958A1 (en) PROSTAGLANDIN ANALOGS WITH TRIPLE BONDING BETWEEN C-13 AND C-14 AND THE METHOD OF MANUFACTURING IT
DE2704959A1 (en) PROSTAGLANDIN ANALOGS WITH TRIPLE BONDING BETWEEN C-13 AND C-14 AND THE METHOD OF MANUFACTURING IT

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C01 Deemed withdrawal of patent application (patent law 1993)
WD01 Invention patent application deemed withdrawn after publication