CN86102630A - The method for preparing 7-amino-3-propenylcephalosporanic acid and ester class thereof - Google Patents
The method for preparing 7-amino-3-propenylcephalosporanic acid and ester class thereof Download PDFInfo
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- CN86102630A CN86102630A CN86102630.6A CN86102630A CN86102630A CN 86102630 A CN86102630 A CN 86102630A CN 86102630 A CN86102630 A CN 86102630A CN 86102630 A CN86102630 A CN 86102630A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/18—7-Aminocephalosporanic or substituted 7-aminocephalosporanic acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/22—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with radicals containing only hydrogen and carbon atoms, attached in position 3
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- 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
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Abstract
The invention provides the novel cephalosporin intermediate, 7 beta-aminos-3-[(Z)-the 1-propylene (1-) base]-3-cephem-4-carboxylic acid and ester class thereof, have above general formula.Wherein the configuration of 3-propenyl is that the Z type claims cis (Cis) sometimes again, and R is hydrogen or common carboxyl-protecting group, and the metal-salt of acid salt and the R above-mentioned substance when being hydrogen.These compounds can be used as the intermediate for preparing orally active cynnematin.
Description
The sequence number that the application proposes for us on December nineteen eighty-three 28 is the part continuation application of 564,604 patent application, and this application now is a United States Patent (USP), the patent No. 4,520, and on May 28th, 022,1985 granted.The patent application in December 28 nineteen eighty-three is to propose January 28 nineteen eighty-three, and existing resigned sequence number is the part continuation application of 461,833 patent application, and sequence number is that 564,604 patent application is disclosed in this as a reference fully.
United Kingdom's patent specification 1,342, No. 241, (corresponding U.S. Patent number is 3,769,277 and 3 to be published on January 3rd, 1974,994,884 respectively on October 30th, 1973, and on November 30th, 1976 granted) disclosed the compound VI, but do not have 7 beta-aminos-3-[(Z)-1-propylene (1) base]-3-cephem-4-carboxylic acid is as the description of the intermediate in the preparation.
United States Patent (USP) 4,409, No. 214 (grant October 11 nineteen eighty-three) disclosed the compound VII and can carried out the Witting reaction and be prepared by the amino 3-trityl group of 7-benzylidene 3-cephem-(4)-carboxylic acid phenylbenzene methyl esters, this mentions in preparation method 38 and 39, but has not both had 7 beta-aminos-3-[(Z)-1-propylene (1) base]-description of 3-cephem-4-carboxylic acid do not have other 3-[1-propylene (1) bases yet] description of cephalosporin compound.
United States Patent (USP) 4,110, No. 534 (on April 29th, 1978 granted) are mentioned especially with Witting prepared in reaction such as VI and these compounds of VII, see 8,9, and 49 hurdles (example 21).
H.O.House etc. (seeing organic chemistry magazine Jour.org.Chem) 29,3327-3333(1964)) studied the influence of the ratio of the cis-form olefin that generates in the Witting reaction of solvent and additive (comprising lithium salts) and trans olefins to aldehyde.
The present invention relates to have the cephalosporin intermediate of formula I, consequent synthetic useful acid salt and metal-salt, and their preparation method.
In the compound of formula I, the configuration of 3-propenyl is Z type or cis, and R is hydrogen or common carboxyl-protecting group.So-called common carboxyl-protecting group is meant the sort of protecting group that is used as protection amino or carboxyl usually in cynnematin is synthetic.Suitable carboxyl-protecting group comprises aralkyl such as benzyl, to a methoxybenzyl, and neighbour-nitrobenzyl, right-nitrobenzyl and diphenyl-methyl (Ph
2CH-); Alkyl such as tert-butyl; Haloalkyl is as 2,2,2-three chloroethyls; alkenyl such as allyl group 2-chlorallyl, alkoxyl-methyl such as methoxymethyl, 2-(three silyls) ethyl; three silyls; the tert-butyl dimethyl silanyl, tert-butyl diphenyl silane base, and described in the literature other carboxyl-protecting groups; for example; in british patent specification 1,399, described in 086.We think the carboxyl-protecting group of removing easily when preferably adopting acid treatment, especially diphenyl-methyl or tert-butyl, and the acid salt of the above-mentioned substance when R is H and metal-salt also are parts of the present invention.
3-propenyl Z type or cis-configuration are the key issues of this compounds.This characteristics determined the cynnematin final product have favourable Grain-negative anti-microbial property, this cynnematin final product is the theme of original application (sequence number 564,604).
Synthetic useful acid salt and comprise formula I and mineral acid example hydrochloric acid, sulfuric acid, phosphoric acid and with organic acid as salt to a toluenesulphonic acids and other acid of in cynnematin technology, being familiar with and adopting generation.
R is that those materials of hydrogen also form metal-salt in the formula I, and the synthetic metal-salt that is suitable for of going up comprises sodium salt, sylvite, calcium salt, magnesium salts, aluminium salt and zinc salt.
The best compound of the present invention is:
1,7 beta-aminos-3-((Z)-1-propylene (1) base)-3-cephem-4-carboxylic acid phenylbenzene methyl esters
2,7 beta-aminos-3-((Z)-1-propylene (1) base)-3-cephem-4-carboxylic acid diphenylmethyl ester hydrochloride
3,7 beta-aminos-3-((Z)-1-propylene (1) base)-3-cephem-4-carboxylic acid phenylbenzene methyl esters vitriol
4,7 beta-aminos-3-((Z)-1-propylene (1) base)-3-cephem-4-carboxylic acid sodium salt
5,7 beta-aminos-3-((Z)-1-propylene (1) base)-3-cephem-4-carboxylic acid sylvite
6,7 beta-aminos-3-((Z)-1-propylene (1-) base)-3-cephem-4-carboxylic acid
Another aspect of the present invention relates to the preparation method of generalformula, and optimum operation is shown in reaction process 1 and 2.
In reaction process 1, diphenyl methyl is used as the optimum protecting group of carboxyl, but other carboxyl-protecting groups as known in the art also can be used.
In the Witting reaction that compound III and acetaldehyde carry out, we find to add suitable lithium halide such as lithium chloride, lithiumbromide or lithium iodide can improve the ratio of Z/E isomer among yield and the reaction product II a, carry out this reaction and should add 5～15 stoichiometric lithiumbromides, preferably 10 stoichiometric lithiumbromides.
Methylene dichloride is best reaction medium, and it preferably contains the solubility promoter such as dimethyl formamide or Virahol than small proportion, and promptly every part of methylene dichloride adds 1/10 to 1/3 part of solubility promoter (by volume) approximately.Range of reaction temperature is advisable with-10 ℃ to+25 ℃, preferably 0 ℃ to 25 ℃.Witting reaction product II a is extracted in the suitable solvent such as ethyl acetate, and extraction liquid promptly gets amino cephem-3 chemical compounds I of 7-of the present invention a with lucky cured the processing toward (Girard) reagent T.Referring to operation 3 herein.Then handle I a with trifluoroacetic acid (TFA) and get 7 beta-aminos-3-((Z)-1-propylene (1) base)-3-cephem-4-carboxylic acid (I b operates 7), the Z/E ratio equals 9/1.Make I b acidylate promptly get oral effective Aneet of (sequence number is 564,604) in the original application with common chloride method or active ester method with right-glycin.
Another route is with uncle N-BOC(-butoxy carbonyl) glycin of protection is at DCC(thricyclohexyl carbodiimide) in the presence of make the 7 beta-aminos-basic cephalosporin ester I of 3-propylene (1) a acidylate, use the TFA(trifluoroacetic acid subsequently) removing protecting group also must Aneet.
The symbol and the meaning that occur in experimental implementation are as follows:
The Ph=phenyl
BOC＝-COO（CH
3）
3
The DCC=dicyclohexyl carbodiimide
The TFA=trifluoroacetic acid
The ETTOAC=ethyl acetate
The DMF=dimethyl formamide
Operation 1
7-benzylidene amino-3-triphenyl phosphorus methyl-3-cephem-(4)-carboxylic acid phenylbenzene methyl esters muriate
At room temperature in the CH of 7-amino-3-chloromethyl-3-cephem-4-carboxylic acid diphenylmethyl ester hydrochloride (200 grams, 0.44 mole)
2Cl
2Add 1N NaOH(440 milliliter in (940 milliliters) suspension).Organic layer is told in mixture jolting 10 minutes.In organic layer, add MgSO
4(75 gram) and phenyl aldehyde (51 grams, 0.48 mole) were at room temperature placed mixture 3 hours.Reaction mixture is filtered, use CH
2Cl
2(200 milliliters) wash insolubles, add triphenylphosphine (126 grams, 0.48 mole) in the amalgamation liquid of filtrate and washing lotion.Mixture under reduced pressure is concentrated into about 400 milliliters, and places 4 days.The viscous oil that is produced dilutes with ethyl acetate (1 liter) and grinds to separate out the compound of this title, and product is light yellow crystallization shape powder, filters and collects, and vacuum-drying gets 322 grams (96%), 185 ° of fusing points-190 ℃ (decomposition).
IR：ν
KBr maxcm
-11780，1720，1630。
UV：
nm（ε）260（24100）
Operation 2
7-benzylidene amino-3-((the inferior phosphoranyl of triphenyl) methyl)-3-cephem-4-carboxylic acid phenylbenzene methyl esters (III)
With 7-benzylidene amino-3-triphenyl phosphorus ylmethyl-3-cephem-4-carboxylic acid phenylbenzene methyl esters muriate (322 grams, 0.42 mole) and 5N Na
2CO
3(252 milliliters) are at CH
2Cl
2Mixture in (1.6 liters) is vigorous stirring 15 minutes at room temperature.Tell organism, use MgSO
4Drying is concentrated to about 500 ml volumes.Enriched material stirs with acetone (1 liter) dilution, obtains the pale yellow crystals powder, filter collect the III of 237 grams (78%), 195～198 ℃ of fusing points (decomposition).
IR：ν
KBr maxcm
-11770，1620。
UV：
nm（ε）254（23000），389（22000）。
NMR：
ppm2.56&3.16（2H，ABq），5.00（1H，d，J＝4 Hz），5.23（1H，d，J＝4 Hz），5.47（1H，d，J＝22 Hz），6.95（1H，s），7.2～7.8（30H，m），8.55（1H，s）。
Operation 8
7-amino-3-((Z)-propylene (1) base)-3-cephem-4-carboxylic acid diphenylmethyl ester hydrochloride (I a hydrochloride).
LiBr(19 gram, 216 mmoles) be dissolved in anhydrous dimethyl formamide (100 milliliters) and CH
2Cl
2In the mixed solvent of (300 milliliters), in this cold soln, add acetaldehyde and 7-benzylidene amino-3-((the inferior phosphoranyl of triphenyl) methyl)-3-cephem-4-carboxylic acid phenylbenzene methyl esters (IV) (15 grams, 20 mmoles) down at-5 ℃.This mixture was placed 20 hours down at-5 °～-10 ℃, at room temperature placed then 5 hours.The gained light brown solution is concentrated into about 100 ml volumes in a vacuum, adds then in the double-deck solvent of ethyl acetate (400 milliliters) and water (400 milliliters) composition.Tell upper solution, with isopropyl ether (400 milliliters) dilution.In mixture, add silica gel (Wako gel C-100,40 grams).Mixture jolting 5 minutes is filtered by the super-cell pad.Mixed solvent with ethyl acetate-isopropyl ether (1/1,200 milliliter) is washed insolubles, and merging filtrate and washing lotion are concentrated into about 400 ml volumes.The solution of Gerald (Girard) reagent T in methyl alcohol (60 milliliters) and acetate (6 milliliters) of 0.5M is added in the above-mentioned concentrated solution, and mixture at room temperature stirred 15 minutes.Mixture is evaporated to about 200 ml volumes, successively water (200 milliliters), saturated NaHCO
3The aqueous solution (3 * 20 milliliters) and salt solution (20 milliliters) are washed, and use MgSO
4Drying is used activated carbon treatment, is concentrated into about 50 milliliters, at room temperature adds 1N methanol hydrochloride solution (40 milliliters) in concentrated solution, allows it place 15 minutes.Mixture is evaporated to about 30 milliliters, and (300 milliliters) dilution adds diethyl ether.Sedimentation and filtration is collected, used P
2O
5Drying gets buff powder 7.9 grams.With the solution activated carbon treatment of this powder (7.3 gram) in methyl alcohol (80 milliliters) and ethyl acetate (80 milliliters) mixed solvent, be concentrated into about 100 milliliters, the crystal of hydrochloride of putting into title compound slowly dilutes with ether (80 milliliters) as crystal seed, stirs one hour.The colourless crystallization of separating out filters to be collected, and uses P in a vacuum
2O
5Dry, to obtain the title compound of 6.3 grams (71%), this product is 3 and goes up Z type and two kinds of mixture of isomers of E type (high pressure liquid chromatography detects Z/E=9/1) that propenyl partly causes, (Lichrosorb RP-18, the phosphate buffered saline buffer of 80% methyl alcohol-pH7.2,254nm, 1 ml/min).
UR：λ
EtOH maxnm（E
1% 1cm）287（173）。
IR：ν
KBr maxcm
-12850，1785，1725。
NMR:
Ppm1.47(27/10H, d-d, J=7,2Hz ,=CHCH
3, cis), 1.74(3/10H, d, J=7Hz ,=CHCH
3, trans), 3.47﹠amp; 3.8(each 1H, d, J=16Hz), and 5.13(1H, d, J=4.5Hz, 6-H), and 5.23(1H, d, J=4.5Hz, 7-H), 5.62(1H, d-q, J=10﹠amp; 7Hz, 3-CH=CH), 6.24(1H, d-d J=10﹠amp; 2Hz, 3-CH), 6.81(1H, s, CHPH
2), 7.35(10H, m, ph-H).
Operation 4
7-amino-3-((Z)-1-propylene (1) base)-the 3-cephem-(I is a) for 4-carboxylic acid phenylbenzene methyl esters
In the suspension that water (20 milliliters) and ethyl acetate (40 milliliters) form, add NaHCO in the 7-amino-3-that is stirring ((Z)-1-propylene (1) base)-3-cephem-4-carboxylic acid diphenylmethyl ester hydrochloride (5 grams, 11.3 mmoles)
3Reach 8 until the pH of mixture value.Wash organic layer with saturated aqueous common salt (5 milliliters), use MgSO
4Drying is concentrated into about 20 ml volumes.Gained solution adds I a crystal seed with isopropyl ether (10 milliliters) dilution.Under agitation slowly add isopropyl ether (30 milliliters) again.After 15 minutes, the colourless crystallization of separating out filters to be collected, and washes with isopropyl ether (10 milliliters), uses P in a vacuum
2O
5Drying, the title compound of 4.3 grams (94%), (high pressure liquid chromatography detect Z/E=9/1), (Lichrosorb RP-18,80% methyl alcohol-pH7.2 phosphate buffered saline buffer, 254nm, 1 ml/min).
IR：ν
KBr maxcm
-13450，1765，1730。
UV：λ
EtOH maxnm（E
1% 1cm）289（185）。
NMR:
Ppm1.43(3H, d-d, J=2﹠amp; 7Hz, CH=CHCH
3), 1.66(2H, br, s, (D disappears
2O), NH
2), 3.23﹠amp; 3.55(each 1H, d, J=17Hz, 2-H), and 4.73(1H, d, J=4.5Hz, 6-H), and 4.96(1H, d, J=4.5Hz, 7-H), 5.46(1H, d-q, J=10﹠amp; 7Hz, 3-CH=CH), 6.06(1H, br, d, J=10Hz, 3-CH), 6.94(1H, s, CHPh
2), 7.3(10H, m, Ph-H).
Operation 5
7-((D)-α-(uncle-butoxy carbonyl amino)-α-(4-hydroxyphenyl) acetamido)-3-((Z)-1-propylene (1) base)-3-cephem-4-carboxylic acid phenylbenzene methyl esters (IV)
7-amino-3-((Z)-1-propylene (1) base)-(I is (4.2 grams a) for 3-cephem-4-carboxylic acid phenylbenzene methyl esters, 10.4 mmole), (D)-α-(tert-butoxycarbonyl amino)-α-(4-hydroxy phenyl) acetate (3.3 grams, 12.5 mmole) and DCC(2.6 gram, 12.5 mmole molecules) mixture in ethyl acetate (104 milliliters) at room temperature stirred 1.5 hours.Mixture is filtered, and insolubles is washed with ethyl acetate (20 milliliters).Filtrate and washing lotion merge, and use saturated NaHCO successively
3The aqueous solution (3 * 5 milliliters), salt solution (5 milliliters), MgSO is used in 10% hydrochloric acid (5 milliliters) and salt washing
4Drying is with activated carbon treatment and filtration.Filtrate is concentrated into about 10 milliliters, with normal heptane (20 milliliters) dilution.Sedimentation and filtration is collected, used P in a vacuum
2O
5Drying gets 7.8 grams (90% purity, colourless powder by weight), (Z/E=9/1 detects according to high pressure liquid chromatography), (LichrosorbRP-18,80% methyl alcohol-pH7.2 phosphate buffered saline buffer, 254nm, 1 ml/min)
IR：ν
KBr maxCm
-13400，1790，1720，1690
UV：λ
EtOH maxnm（E
1% 1cm）278（113），289（115），295（95）
NMR:
Ppm1.3-1.45(12H, m, BOC-H﹠amp;=CH
3-CH
3), 3.08﹠amp; 3.33(each 1H, d, J=18Hz, 2-H), and 4.92(1H, d, J=4.5Hz, 6-H), 5.06(1H, d, J=6Hz, S(D
2O), CHN), 5.5(1H, d-q, J=10﹠amp; 7Hz, 3-CH=CH), 5.68(1H, d-d, J=4.5﹠amp; 8Hz.d, J=4.5Hz(D
2O), 7-H), 6.01(1H, d, J=10Hz, 3-CH), 6.65﹠amp; 7.08(each 2H, d, J=8Hz, HO
) 6.71(1H, d, J=8Hz, (D disappears
2O), 7-NH
2), 6.88(1H, s, CHPh
2), 7.3(10H, m, Ph-H).
Operation 6
BMY-28100; 7-((D)-and 2-amino-2-(4-hydroxy phenyl) acetamido)-3-(propylene (1) base)-3-cephem-4-carboxylic acid (V)
With the 7-((D)-α-(uncle-butoxy carbonyl amino)-α-(4-hydroxy phenyl) acetamido) of operation 5 preparations-3-((Z)-1-propylene (1-) base)-3-cephem-4-carboxylic acid phenylbenzene methyl esters (IV) (purity 90%, 7.7 gram, 10.6 mmole), the mixture with phenylmethylether (7.7 milliliters) and trifluoroacetic acid (77 milliliters) at room temperature stirred 1 hour.Mixture is concentrated in a vacuum.Toluene (50 milliliters) is added in the concentrated solution, and mixture evaporates in a vacuum.Ether (200 milliliters) is added oil residues.The solid filtering of separating out is collected, and washes with ether (20 milliliters), uses the KOH drying in a vacuum, with trifluoroacetate 5.3 grams that obtain BMY-28100.In this salt (5.3 gram) water-soluble (100 milliliters), use activated carbon treatment, be placed on and loaded Diaion HP-20(0.6 liter) post on, use H
2The O(4 liter) wash, use 40% aqueous methanol wash-out again, collection contains the meoh eluate (1.7 liters) of required product, and is evaporated to about 20 ml volumes.Concentrated solution slowly dilutes with acetone (100 milliliters).The colourless crystallization shape powder filter of separating out is collected, washed with acetone (20 milliliters), and use P in a vacuum
2O
5Drying gets 4 BMY-28100(Z/E=9/1 that restrain, zwitter-ion) (Lichrosorb RP-18,20% methyl alcohol-pH7.2 phosphate buffered saline buffer, 254nm, 1 ml/min).
Operation 7
7-amino-3-((Z)-and 1-propylene (1) base) cephem-3-alkene-4-carboxylic acid, I b
In the solution that is cooled to 260 milliliters of phenylmethylethers of 0 ℃ and 1.38 liters of trifluoroacetic acids that is stirring, add 7-amino-3-(((Z)-1-propylene (1) the base)-3-cephem-4-carboxylic acid diphenylmethyl ester hydrochloride (0.388 mole) (operation 3 or 11) of 149.7 grams (0.338 mole).Then the soup compound that obtains was at room temperature stirred one hour.Under vacuum, remove most of unnecessary trifluoroacetic acid with the rotation vaporizer.The residual supernatant liquor that inclines, residual soup compound ground one hour with 1.5 liters anhydrous diethyl ether.Crystallized product is filtered, use P
2O
5Drying, the trifluoroacetate of 87.24 gram I b.The trifluoroacetate of these 87.24 grams is suspended in 900 ml waters and stirs (pH is about 2.5).Mixture is cooled to+and 5 ℃, regulate pH value to 0.6 with 12N HCl then.The yellow solution activated carbon treatment, soup compound filters on diatomite flocculating aids pad.Gained solution is cooled to+and 5 ℃, with 20% sodium hydroxide pH is transferred to 2.0.Solution is placed in refrigerator and was made it crystallization in one hour.Collect crystallization, use 800 ml waters, 800 milliliters of acetone are washed, and vacuum-drying at room temperature, get 69.4 grams (85.5%), contain 9.7% trans-isomer(ide) (high pressure liquid chromatography detection, pillar model RP-18 MERCK; H
2(NH
4) PO
40.1 95 milliliters+CH of mole
3The CN5 milliliter detects at 290nm).
Operation 8
7-amino-3-((Z)-1-propylene (1) base)-3-cephem-4-carboxylic acid, I b
To operate 2 gained phosphoranyl compound III (50.0 grams, 68.7 mmoles) at CH
2Cl
2Solution in (500 milliliters) and lithiumbromide (29.8 grams, 343 mmoles) are containing a small amount of CH
2Cl
2Solution in the dry DMF of (10 milliliters) (170 milliliters) mixes, then with anhydrous acetaldehyde (39 milliliters, 687 mmoles, press N.L.Drake and G.B.COOke, Org, Syn, Col.Vol. II, the operation of P407 is made by paraldehyde and toluenesulphonic acids distillation) mix.Mixture was placed 2 days down at 20 ℃ in an airtight container.Reaction mixture is evaporated; debris is diluted with ethyl acetate (800 milliliters); water (3 * 300 milliliters) and saturated NaCl solution (300 milliliters) are washed; and evaporate 3-propenyl derivatives II a to be protected; be spumescence solid (34 gram) that this product does not need further pure system promptly to can be used for next step reaction.
The II a raw material that obtains was above at room temperature handled one hour with 98% formic acid (35 milliliters) and concentrated hydrochloric acid (17 milliliters, 206 mmoles).In reaction mixture, add entry (350 milliliters) with a minute oil-yielding stratum, oil reservoir ethyl acetate (3 * 100 milliliters) flush away.The pH of water layer under agitation uses about 65 milliliters of 4N NaOH() be adjusted to about 3, to produce crystalline solid, this solid filtering is collected, and water (50 milliliters) is washed, and promptly gets title compound (I b, 9.7 gram, 59%), high pressure liquid chromatography detects (Liehro-sorb RP-18,4 * 300mm, MeOH: phosphate buffered saline buffer (pH7)=15: 85) show that this product is Z type and two kinds of mixture of isomers of E type that the two keys of 3-propenyl cause, the ratio of its Z and E is 83: 17.200 ℃ of fusing points (decomposition).
IR：ν
max（KBr）incm
-13420，1805，1620.
UV：λ
max（pH 7 phosphate buffer）in nm（ε）283（8900）.
PMR：δ（D
2O+NaHCO
3）in ppm 1.69 and 1.88（3H，each d，J＝6.0 Hz，Z and E of -CH＝CH-CH
3），3.38 and 3.72（2H，Abq，J＝17 Hz，H-2），5.18（1H，d，J
6，7＝5.0 Hz，H-6），5.51（1H，dH-7），ca.5.8（1H，m，-CH＝CH-CH
3）and 6.06（1H，d，J＝11Hz，-CH＝CH-CH
3）.
Calculate: C
10H
12N
2O
3S:C, 49.99; H, 5.03; N, 11.66;
S，13.34%.
Actual measurement: C, 50.20; H, 4.94; N, 10.93;
S，12.82%.
Operation 9
7-((D)-and 2-amino-2-(4-hydroxy phenyl) acetamido)-3-(Z)-and 1-propylene (1-) base)-3-cephem-4-carboxylic acid, V
With xylidene(s) (1.7 milliliters, 13.1 mmoles), chloro trimethyl silane (2.1 milliliters, 16.4 mmoles) and triethylamine (2.3 milliliters of TEA, 16.4 mmoles) add by operation 8 prepared I b successively at CH under ice-cold condition
2Cl
2In the suspension of (16 milliliters).Mixture at room temperature stirred 30 minutes.In mixture, under stirring state, add in batches D-right-hydroxy phenyl glycyl chloride hydrochloride (1.46 the gram, 6.56 mmole), reaction is by high pressure liquid chromatography (Lichro-sorb RP-18,4 * 300mm, MeOH: monitoring phosphate buffered saline buffer (pH7)=25: 75).Divide a certain amount of glycyl chloride of another part three times and add in the said mixture, added once, add 291 milligrams at every turn, acidylate fully every 15 minutes.Contain the anhydrous methanol (2.0 milliliters) of dry DMF (0.1 milliliter) in adding after, the gained clear solution is used CH then with triethylamine (3.2 milliliters) pH6 that neutralizes
2Cl
2(30 milliliters) dilution is collected sedimentation and filtration to separate out precipitation, uses CH
2Cl
2(10 milliliters) are washed, and get the solvent dimethylformamide thing of title compound, (2.39 grams, yield 94%, about 50% purity, Z/E=47: 12, high pressure liquid chromatography detects).
Operation 10
7-phenyl-acetamides base-3-((Z)-propylene (1-) base) cephalo-3-alkene-4-carboxylic acid phenylbenzene methyl esters, IV.
With 18 liters of CCl that stirring
4, the solution of 1.8 liters of methyl alcohol and the right-benzoylbenzoic acid of 12 grams are cooled to 8 ℃, add 970 milliliters of acetaldehyde.The temperature of gained solution rises to+and 14 ℃.After 5 minutes, add 588 gram (0.7749 mole) 7-phenyl-acetamides-3-((the inferior phosphoranyl of triphenyl) methyl)-3-cephem-4-carboxylic acid phenylbenzene methyl esters.Remove cooling bath, with mixture under 35 ℃, in lucifuge with at N
2Under the atmosphere, vigorous stirring 4 hours is till positive phosphine compound dissolves fully.
The solution that obtains concentrates in a vacuum, and residue is dissolved in 2 liters of ethanol, and being concentrated into residue more in a vacuum, to be half hitch crystalline, then with 3 liters of ethanol furnishing pulpous states.
Mixture stirred 2 hours down at+5 ℃, allowed its placement spend the night, and crystallization collects twice, washes with ethanol, and at room temperature carries out vacuum-drying.Product is 191 grams (47%), fusing point 124-128 ℃, contains 7.5% trans-isomer(ide) (detected by high pressure liquid chromatography, pillar model Lichrosorb Si 60 5 μ m Merck are with 85% toluene, 15% eluent ethyl acetate).
Operation 11
7-amino-3-((Z)-propylene (1-) base) cephalo-3-alkene-4-carboxylic acid diphenylmethyl ester hydrochloride, I a
PCl with 159.7 grams (0.767 mole)
5Be dissolved in 2.8 liters CH
2Cl
2In, under condition of stirring, in 20 minutes, the pyridine that adds 56.7 milliliters (0.700 moles) is at 280 milliliters of CH
2Cl
2In solution.At N
2Under the atmosphere, soup compound is cooled to+2 ℃, adds 256 gram (0.488 mole) IX that operation 10 makes.Mixture was stirred 40 minutes the soup compound that is produced 1.4 liters of CH that rapid impouring vigorous stirring under-20 ℃
2Cl
2In the 1.3-butanediol solution of 204 milliliters (2.33 mmoles), make temperature be no more than-5 ℃.Remove cooling bath, after 45 ℃ minutes, temperature rises to 10 ℃, keeps this temperature to reach 35 minutes, add water (1 liter), continue to stir 5 minutes, allow its layering afterwards, organic layer is washed with 400 milliliters of saturated common salts then with 600 milliliters of 2N hydrochloric acid, and the water layer of merging is used 2 * 600 milliliters of CH again
2Cl
2Former CH is incorporated in backwash, washing lotion into
2Cl
2Extracting solution.
The anhydrous MgSO of solution
4Drying is with pulpous state MgSO
4Filter, with 2 * 500 milliliters of CH
2Cl
2Wash, the filtrate of merging rises volume with rotation vaporizer vacuum concentration to 2.4, and dilutes with 2.5 liters of ethyl acetate.Solution is concentrated into about 1.3 liters of volumes once more.Crystallization-the soup compound that is produced is filtered, wash, use P with 3 * 300 milliliters of ethyl acetate
2O
5After carrying out dry air and vacuum-drying, get title compound 149.8 grams, be the brown crystallization, yield 69.3%.
Claims (10)
1, preparation has the compound of following structural formula
The method of the metal-salt of the above-mentioned substance when (wherein the 3-propenyl has the Z configuration, and R is hydrogen or common carboxyl-protecting group), its acid salt and R are hydrogen, this method comprises makes the intermediate with following structural
(wherein the implication of R is identical with top specified implication, ph is a phenyl) react in the inert organic reaction medium with acetaldehyde, this medium includes methylene dichloride, N, N '-dimethyl formamide, Virahol or their mixture, temperature of reaction are between 0 ℃ to 25 ℃, to produce the compound of representing with following formula
Slough benzylidene then or slough benzylidene and carboxylic acid protecting group simultaneously, if desired, separate 3-(Z) and 3-(E) isomer again, to produce the compound of representing with following formula
Wherein the implication of R is same as described above.
2, the described method of claim 1, wherein R system is selected from hydrogen, methoxymethyl, 2,2,2-three chloroethyls, the 2-(front three is to alkyl) ethyl, the tertiary butyl, benzyl, diphenyl methyl, neighbour-nitrobenzyl, right-nitrobenzyl, front three silicon benzyl, tertiary butyl dimethyl silanyl, tertiary butyl quadrosilan base, allyl group, the group of 2-chlorallyl.
3, the described method of claim 2, wherein acid salt system is selected from hydrochloride, and vitriol is right-tosylate, phosphoric acid salt.
4, the described method of claim 1, wherein metal-salt is a sodium salt, sylvite, calcium salt or aluminium salt.
5, the described method of claim 2, wherein compound is 7 beta-aminos-3[(Z)-1-propylene (1) base-3-cephem-4-carboxylic acid phenylbenzene methyl esters, and hydrochloride.
6, the described method of claim 2, compound wherein are 7 beta-aminos-3[(Z)-1-propylene (1-) base-3-cephem-4-carboxylic acid and hydrochloride thereof.
7, the described method of claim 4, compound wherein are 7 beta-aminos-3[(Z)-1-propylene (1-) base-3-cephem-4-carboxylic acid sodium salt.
8, the described method of claim 1 is wherein carried out in the presence of the fontanel lithium with the reaction of acetaldehyde.
9, the described method of claim 8, wherein the fontanel lithium is a lithium chloride, lithiumbromide or lithium iodide.
10, the described method of claim 8, wherein the fontanel lithium is a lithiumbromide.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US72587185A | 1985-04-22 | 1985-04-22 | |
| US725,871 | 1985-04-22 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN86102630A true CN86102630A (en) | 1987-02-04 |
| CN1015714B CN1015714B (en) | 1992-03-04 |
Family
ID=24916301
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN86102630A Expired CN1015714B (en) | 1985-04-22 | 1986-04-21 | Prepn. of 7-amino-3-propenylcephalosporanic acid and esters thereof |
Country Status (38)
| Country | Link |
|---|---|
| JP (1) | JPS61249989A (en) |
| KR (1) | KR860008189A (en) |
| CN (1) | CN1015714B (en) |
| AR (1) | AR242581A1 (en) |
| AT (1) | AT392072B (en) |
| AU (1) | AU589170B2 (en) |
| BE (1) | BE904646A (en) |
| CA (1) | CA1273629A (en) |
| CH (1) | CH671399A5 (en) |
| CS (1) | CS270435B2 (en) |
| CY (1) | CY1571A (en) |
| DD (1) | DD244557A5 (en) |
| DE (1) | DE3613365A1 (en) |
| DK (1) | DK163584C (en) |
| EG (1) | EG18001A (en) |
| ES (1) | ES8800236A1 (en) |
| FI (1) | FI84268C (en) |
| FR (1) | FR2580652B1 (en) |
| GB (1) | GB2173798B (en) |
| GR (1) | GR861065B (en) |
| HK (1) | HK106290A (en) |
| HU (1) | HU195223B (en) |
| IE (1) | IE59014B1 (en) |
| IT (1) | IT1228241B (en) |
| LU (1) | LU86402A1 (en) |
| MY (1) | MY100694A (en) |
| NL (1) | NL192205C (en) |
| NO (1) | NO164659C (en) |
| NZ (1) | NZ215717A (en) |
| OA (1) | OA08245A (en) |
| PT (1) | PT82436B (en) |
| SE (1) | SE500217C2 (en) |
| SG (1) | SG90890G (en) |
| SU (1) | SU1435155A3 (en) |
| YU (1) | YU43697B (en) |
| ZA (1) | ZA862985B (en) |
| ZM (1) | ZM4286A1 (en) |
| ZW (1) | ZW9086A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103183686A (en) * | 2011-12-30 | 2013-07-03 | 浙江新和成股份有限公司 | Preparation method of 7beta-amino-7lapha-methoxy-3-cephem compound |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4708955A (en) * | 1985-06-24 | 1987-11-24 | Bristol-Myers Company | 3-(substituted)propenyl-7-aminothiazol-ylcephalosporanic acids and esters thereof |
| US4870168A (en) * | 1987-02-26 | 1989-09-26 | Bristol-Myers Company | 3-Unsaturated alkyl cephems from 3-triflyl cephems |
| DE3933934A1 (en) * | 1989-10-03 | 1991-04-11 | Bayer Ag | METHOD FOR PRODUCING 7-AMINO-3 - ((Z) -1-PROPEN-1-YL) -3-CEPHEM-4-CARBONIC ACID |
| DE69231815T2 (en) * | 1991-03-08 | 2001-09-27 | Biochemie Gmbh | Process for the preparation of cephalosporins and intermediates in this process |
| AT399876B (en) * | 1992-02-05 | 1995-08-25 | Biochemie Gmbh | Purificn. of 7-amino-3-((z)-1-propen-1-yl)-3 -cephem-4-carboxylic acid - useful in prodn. of broadband antibiotics |
| KR950700311A (en) * | 1992-02-05 | 1995-01-16 | 게오르게스 그렐리니, 한스 루돌프하우스 | Process for the purification of a 3-cephem-4-carboxylic acid derivatives |
| JPH07173168A (en) * | 1993-07-14 | 1995-07-11 | Sumitomo Chem Co Ltd | Cephem compound, its production and utilization of the compound for production of cephem antibiotic substance |
| AU2003267733A1 (en) * | 2002-10-08 | 2004-05-04 | Ranbaxy Laboratories Limited | Process for the preparation of (z)-isomer enriched 7-amino-3-propen-1-yl-3-cephem-4- carboxylic acid |
| EP1678186A4 (en) * | 2003-10-30 | 2007-04-25 | Cj Corp | Processes for the preparation of cephem derivatives |
| JP4046708B2 (en) * | 2004-06-04 | 2008-02-13 | 明治製菓株式会社 | Method for producing 3-alkenylcephem compound |
| US20080281093A1 (en) | 2004-11-01 | 2008-11-13 | Bandi Parthasaradhi Reddy | Novel Process For Preparation of Cefprozil Intermediate |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1342241A (en) * | 1970-01-23 | 1974-01-03 | Glaxo Lab Ltd | Cephalosporin compounds |
| US4110534A (en) * | 1970-01-23 | 1978-08-29 | Glaxo Laboratories Limited | Process for the preparation of 3-vinyl and substituted vinyl cephalosporins |
| US3769277A (en) * | 1970-01-23 | 1973-10-30 | Glaxo Lab Ltd | Preparation of delta3-4 carboxy cephalosporins having a 3-vinyl or substituted 3-vinyl group |
| US4065620A (en) * | 1971-06-14 | 1977-12-27 | Eli Lilly And Company | 3-(Substituted) vinyl cephalosporins |
| US4409214A (en) * | 1979-11-19 | 1983-10-11 | Fujisawa Pharmaceutical, Co., Ltd. | 7-Acylamino-3-vinylcephalosporanic acid derivatives and processes for the preparation thereof |
| US4520022A (en) * | 1983-01-28 | 1985-05-28 | Bristol-Myers Company | Substituted vinyl cephalosporins |
| AU566944B2 (en) * | 1983-10-07 | 1987-11-05 | Gist-Brocades N.V. | Preparation of 3-cephem derivatives |
-
1986
- 1986-03-21 FR FR8604051A patent/FR2580652B1/en not_active Expired
- 1986-04-07 NZ NZ215717A patent/NZ215717A/en unknown
- 1986-04-11 NO NO861430A patent/NO164659C/en unknown
- 1986-04-16 SU SU864027263A patent/SU1435155A3/en active
- 1986-04-16 AU AU56168/86A patent/AU589170B2/en not_active Expired
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- 1986-04-18 AR AR86303699A patent/AR242581A1/en active
- 1986-04-18 CA CA000507037A patent/CA1273629A/en not_active Expired - Lifetime
- 1986-04-21 ZM ZM42/86A patent/ZM4286A1/en unknown
- 1986-04-21 CN CN86102630A patent/CN1015714B/en not_active Expired
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- 1986-04-21 IE IE104886A patent/IE59014B1/en not_active IP Right Cessation
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- 1986-04-21 PT PT82436A patent/PT82436B/en unknown
- 1986-04-21 BE BE0/216572A patent/BE904646A/en not_active IP Right Cessation
- 1986-04-21 IT IT8620162A patent/IT1228241B/en active
- 1986-04-21 DD DD86289446A patent/DD244557A5/en unknown
- 1986-04-21 SE SE8601825A patent/SE500217C2/en not_active IP Right Cessation
- 1986-04-21 CH CH1601/86A patent/CH671399A5/de not_active IP Right Cessation
- 1986-04-21 NL NL8601011A patent/NL192205C/en not_active IP Right Cessation
- 1986-04-21 DE DE19863613365 patent/DE3613365A1/en active Granted
- 1986-04-21 ES ES554215A patent/ES8800236A1/en not_active Expired
- 1986-04-21 CS CS862872A patent/CS270435B2/en not_active IP Right Cessation
- 1986-04-21 GB GB08609661A patent/GB2173798B/en not_active Expired
- 1986-04-21 LU LU86402A patent/LU86402A1/en unknown
- 1986-04-22 GR GR861065A patent/GR861065B/en unknown
- 1986-04-22 AT AT0106786A patent/AT392072B/en not_active IP Right Cessation
- 1986-04-22 JP JP61091419A patent/JPS61249989A/en active Granted
- 1986-04-22 YU YU659/86A patent/YU43697B/en unknown
- 1986-04-22 KR KR1019860003085A patent/KR860008189A/en not_active Application Discontinuation
-
1987
- 1987-09-29 MY MYPI87002270A patent/MY100694A/en unknown
-
1990
- 1990-11-09 SG SG908/90A patent/SG90890G/en unknown
- 1990-12-18 HK HK1062/90A patent/HK106290A/en not_active IP Right Cessation
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103183686A (en) * | 2011-12-30 | 2013-07-03 | 浙江新和成股份有限公司 | Preparation method of 7beta-amino-7lapha-methoxy-3-cephem compound |
| CN103183686B (en) * | 2011-12-30 | 2016-06-29 | 浙江新和成股份有限公司 | The preparation method of 7 beta-amino-7 α-methoxyl group-3-cephem compounds |
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