CN1192025C - Method for preparing substituted 4-phenyl-4-cyanocyclohexanoic acids - Google Patents

Method for preparing substituted 4-phenyl-4-cyanocyclohexanoic acids Download PDF

Info

Publication number
CN1192025C
CN1192025C CNB988100304A CN98810030A CN1192025C CN 1192025 C CN1192025 C CN 1192025C CN B988100304 A CNB988100304 A CN B988100304A CN 98810030 A CN98810030 A CN 98810030A CN 1192025 C CN1192025 C CN 1192025C
Authority
CN
China
Prior art keywords
formula
compound
randomly
water
hydrogen
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.)
Expired - Fee Related
Application number
CNB988100304A
Other languages
Chinese (zh)
Other versions
CN1275052A (en
Inventor
K·维布
W·门德森
J·陈
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.)
SmithKline Beecham Corp
Original Assignee
SmithKline Beecham Corp
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 SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Publication of CN1275052A publication Critical patent/CN1275052A/en
Application granted granted Critical
Publication of CN1192025C publication Critical patent/CN1192025C/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/48—Compounds containing oxirane rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/45—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C255/46—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of non-condensed rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
    • C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
    • C07C47/575—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pulmonology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

This invention relates to a method of preparing a compound type where at least one of R' or R'' is a carboxyl group (I) by treating a compound of formula (II) with a Group I(a) or Group II(a) metal halide, with an aprotic dipolar amide-based solvent and water.

Description

The preparation method who replaces 4-phenyl-4-cyanocyclohexanoic alkane carboxylic acid
Invention field
The present invention relates to prepare the intermediate and the synthetic route of 4-cyano group-4-(3-cyclopentyloxy-4-p-methoxy-phenyl) hexahydrobenzoic acid and its analogue.This acid and analogue thereof optionally suppress the catalytic site among the phosphodiesterase isoenzyme IV (name) (hereinafter claiming PDE IV), so this acid is used for the treatment of multiple by influencing the disease that PDE IV enzyme and hypotype thereof are alleviated.
Background of invention
Bronchial asthma is a kind of multifactor property disease of complexity, it is characterized in that the hyperergy of the narrow and respiratory tract of the reversibility of air flue to outside stimulus.
Because multiple mediators plays effect in the development of this disease, make people be difficult to discern new treating asthma medicine.Therefore, will to play obvious effect to all main bronchial asthma origin causes of formation be to seem impossible in the effect of eliminating a kind of mediators.The another kind of implication of " mediators taps into " is to regulate the cell response activity corresponding to the disease physiopathology.
A kind of approach is by improving the level of cAMP (ring 3 ', 5 '-adenylic acid).According to the show, ring AMP is the second messenger of mediation to the biological response of multiple hormone, neurotransmitter and medicine; [Krebs Endocrinology Proceedings of the 4th InternationalCongress Excerpta Medica, 17-29,1973].When suitable antagonist combined with the specific cell surface receptor, adenylate cyclase was activated, Mg + 2-ATP is accelerated and is converted into cAMP.
Ring AMP regulates great majority, but is not the cytoactive of whole physiopathology generation effects to exogenous (allergy) asthma.Therefore the raising of cAMP level will produce beneficial effect, comprise: 1) airway smooth muscle is lax, 2) suppress the release of mast cell mediated thing, 3) suppress neutrophil cell threshing, 4) suppress basophilic leukocyte threshing and 5) activation of inhibition monocyte and scavenger cell.Therefore, the compound of activated adenyl cyclase or inhibition phosphodiesterase will effectively suppress the inappropriate activation of airway smooth muscle and various inflammatory cells.The main cell mechanism of cAMP inactivation is that 3 '-phosphodiester bond is called the isozyme hydrolysis of the gang of cyclic nucleotide phosphodiesterase (PDEs) by one or more.
According to showing, a kind of cyclic nucleotide phosphodiesterase (PDE) isozyme PDE IV ruptures to the cAMP in airway smooth muscle and the inflammatory cell and works.[Torphy, " phosphodiesterase isoenzyme: the potential target position of new anti-asthmatic medicament ", " asthma new drug " (New Drugs for Asthma), Barnes edits, IBC Technical Services Ltd., 1989].Studies show that the restraining effect to this enzyme not only makes airway smooth muscle lax, also suppresses the threshing of mastocyte, basophilic leukocyte and neutrophil cell, and suppresses the activation of monocyte and neutrophil cell.In addition, in vivo, when the nucleotide cyclase of target cell active because suitable hormone or increta improve, the beneficial effect of PDE IV inhibitor will be strengthened significantly.Like this, PDE IV inhibitor will be effective to the asthma lung, the PGE in the asthma lung 2And prostacyclin (activator of adenylate cyclase) level raises.This compounds will provide the class of medications of uniqueness with treatment bronchial asthma, compare with medicine in the market, and they have the obvious treatment superiority.
Method of the present invention and intermediate provide preparation some 4-replacement-4-(3, the 4-di-substituted-phenyl) means of hexahydrobenzoic acid, and they are used for the treatment of asthma and other can be by influencing the disease that PDE IV enzyme and hypotype thereof are alleviated.In the United States Patent (USP) of publishing on September 3rd, 1,996 5552483, described comprehensively and made us interested end product especially.Wherein disclosed for understanding the present invention and putting into practice information essential to the invention and content all is incorporated herein by reference.
Summary of the invention
The present invention relates to the method for preparation I compound,
Wherein
R 1Be-(CR 4R 5) nC (O) O (CR 4R 5) mR 6,-(CR 4R 5) nC (O) NR 4(CR 4R 5) mR 6,-(CR 4R 5) nO (CR 4R 5) mR 6Or-(CR 4R 5) rR 6, wherein moieties can be chosen wantonly by one or more halogens and replace;
M is 0 to 2;
N is 1 to 4;
R is 0 to 6;
R 4And R 5Be independently selected from hydrogen or C 1-2Alkyl;
R 6Be aryl, the aryloxy C of hydrogen, methyl, hydroxyl, aryl, halogen replacement 1-3The aryloxy C that alkyl, halogen replace 1-3Alkyl, 2,3-indanyl, indenyl, C 7-11Multi-ring alkyl, tetrahydrofuran (THF), furyl, THP trtrahydropyranyl, pyranyl, tetrahydro-thienyl, thienyl, tetrahydro thiapyran base, thiapyran base, C 3-6Cycloalkyl or comprise the C of one or two unsaturated link(age) 4-6Cycloalkyl, cycloalkyl wherein and heterocyclic radical part can randomly be replaced by 1 to 3 methyl or an ethyl;
Condition is:
A) work as R 6When being hydroxyl, then m is 2; Perhaps
B) work as R 6When being hydroxyl, then r is 2 to 6; Perhaps
C) work as R 6When being 2-THP trtrahydropyranyl, 2-tetrahydro thiapyran base, 2-tetrahydrofuran base or 2-tetrahydro-thienyl, then m is 1 or 2; Perhaps
D) work as R 6When being 2-THP trtrahydropyranyl, 2-tetrahydro thiapyran base, 2-tetrahydrofuran base or 2-tetrahydro-thienyl, then r is 1 to 6; Perhaps
E) when n be 1 and m when being 0, then-(CR 4R 5) nO (CR 4R 5) mIn R 6Not H;
X is YR 2, halogen, nitro, NH 2Or methane amide;
X 2Be O or NR 8
Y is O or S (O) M '
M ' is 0,1 or 2;
R 2Be independently selected from can be randomly by one or more halogens replace-CH 3Or-CH 2CH 3
R 3Be hydrogen, halogen, C 1-4Alkyl, CH 2NHC (O) C (O) NH 2, the C that replaces of halogen 1-4Alkyl ,-CH=CR 8 'R 8 ', can be randomly by R 8 'The cyclopropyl, CN, the OR that replace 8, CH 2OR 8, NR 8R 10, CH 2NR 8R 10, C (Z ') H, C (O) OR 8, C (O) NR 8R 10Or C ≡ CR 8 '
R 8Be hydrogen or the C that can be randomly replaced by one to three fluorine 1-4Alkyl;
R 8 'Be R 8Or fluorine;
R 10Be OR 8Or R 11
R 11Be hydrogen or the C that can be randomly replaced by one to three fluorine 1-4Alkyl;
Z ' is O, NR 9, NOR 8, NCN, C (CN) 2, CR 8CN, CR 8NO 2, CR 8C (O) OR 8, CR 8C (O) NR 8R 8, C (CN) NO 2, C (CN) C (O) OR 9Or C (CN) C (O) NR 8R 8
R ' and R " be independently selected from hydrogen or-C (O) OX, wherein X is hydrogen or metal or ammonium cation;
This method comprises:
A) with I (a) family or II (a) family's metal halide and a kind of compound of not having proton dipole amide group solvent and water and formula A or B,
Among formula A and the B, R 1, R 3, X 2Has identical meanings in the formula (I) with X;
B) described mixture is heated a few hours at least 60 ℃, this heating can be chosen wantonly under inert atmosphere and carry out;
C) add highly basic in the described mixture and be settled out formula (I) mixture;
D) from described precipitation, remove deamidate solvent and water, and randomly
1) be further purified precipitation, or
2) make sedimentation acidified, obtain free acid.
Invent concrete scheme
Method of the present invention relates to the synthetic of some 4-replacement-4-(3, the 4-di-substituted-phenyl) hexahydrobenzoic acid.Make the cyano group epoxide be converted into required respective acids by I (a) family or II (b) family salt intermediate.
Adopting the compound of this method preparation is PDE IV inhibitor.They are used for the treatment of the multiple disease of describing in the laid-open U.S. Patents 5552438 on September 3rd, 1996.
It is following can adopting the preferred compound of this method preparation:
In the molecular formula compound of all names, preferred R 1Substituting group is CH 2-cyclopropyl, CH 2-C 5-6Cycloalkyl, C unsubstituted or that replaced by OH 4-6Cycloalkyl, C 7-11Multi-ring alkyl, (3-or 4-cyclopentenyl), phenyl, tetrahydrofuran (THF)-3-base, benzyl or C unsubstituted or that replaced by one or more fluorine 1-2Alkyl ,-(CH 2) 1-3C (O) O (CH 2) 0-2CH 3,-(CH 2) 1-3O (CH 2) 0-2CH 3With-(CH 2) 2-4OH.
Formula (I) or (II) in, preferred X group be those wherein X be YR 2And Y is the group of oxygen.In the formula (I), preferred X 2Group is those wherein X 2It is the group of oxygen.Preferred R 2Group is C unsubstituted or that replaced by one or more halogens 1-2Alkyl.Halogen atom is fluorine and chlorine preferably, is more preferably fluorine.Preferred R 2Group is alkyl, the especially C that methyl or fluorine replace 1-2Alkyl, for example-CF 3,-CHF 2Or-CH 2CHF 2Most preferably-CHF 2With-CH 3
Most preferably those compounds, wherein R 1Be-CH 2-cyclopropyl, cyclopentyl, 3-hydroxycyclopent base, methyl or CF 2H; X is YR 2Y is an oxygen; X 2Be oxygen; R 2Be CF 2H or methyl; And R 3It is the compound of CN.
The lithium salts of these compounds is represented the preferred compound of a group.The lithium salts of 4-cyano group-4-(3-cyclopentyloxy-4-p-methoxy-phenyl)-γ-1-hexahydrobenzoic acid particularly, promptly 4-cyano group-4-(3-cyclopentyloxy-4-p-methoxy-phenyl)-γ-1-hexahydrobenzoic acid lithium has been represented a kind of preferred scheme.Especially, compound cis 4-cyano group-4-(3-cyclopentyloxy-4-p-methoxy-phenyl)-γ-1-hexahydrobenzoic acid lithium is most preferred.
Carboxylate salt is preparation like this: with I (a) family or II (a) family metal halide open loop epoxide, obtain acyl cyanide, in the presence of water acyl cyanide is hydrolyzed to acid.A problem with acyl cyanide preparation acid is when acyl cyanide forms carboxylate salt, produces prussic acid (HCN).Require to adopt the rational means of cost-efficient to remove this HCN.Characteristics of the present invention are more effectively to remove HCN.The inventor finds, carries out if be reflected in the aqueous no proton dipole amide group solvent, and when adding highly basic, cyanide salt forms and is retained in the solution, forms the carboxylate salt precipitation simultaneously at solution.So collecting precipitation also removes and desolvates, and also promptly means from the alkanoate precipitation and has removed most of or all basically cyanide salts.This has been avoided having to carry out extra purification step, for example oxidation HCN.
I that uses among the present invention (a) or II (a) family metal halide are any basic metal or alkaline-earth metal, i.e. lithium, sodium, potassium, rubidium, caesium or francium; Halogenide with beryllium, magnesium, calcium, strontium, barium or radium.Preferred metal is lithium and magnesium.Halogenide comprises fluorochemical, muriate, bromide and iodide.Preferred halogenide is bromide.The halogenide of preferred lithium and magnesium.Lithiumbromide and magnesium bromide are most preferred.Especially preferred lithiumbromide.
About the amide group solvent, can enumerate dimethyl formamide (DMF), N,N-DIMETHYLACETAMIDE and N-Methyl pyrrolidone.DMF is most preferred.Except that the amide group solvent, also can use second kind of solvent.For example acetonitrile is successfully used in the following reaction.Usually water is added in the retort, the hydrolysis acyl cyanide obtains paraffinic acid on the spot.Another preferred version of the present invention is to use the mixable aprotic dipolar solvent of water.DMF, N,N-DIMETHYLACETAMIDE and N-Methyl pyrrolidone meet this requirement.Though in reaction medium water must be arranged, the amount of water can differ greatly.Even when the water that exists in a small amount, reaction still can be carried out.In reaction vessel, the preferred water that accounts at least 0.1% (w/w) of any liquid and solid amount in the container that exists.The preferred water yield is at least about 1%w/w, most preferably is about 1-5%w/w.Though the mixed solvent system of all possible water and amide group solvent is not tested, known that this reaction can carry out when having 20% (w/w) water.Therefore, think the water that can use higher per-cent.The practitioner in the art can be known the optimum proportion of organic solvent and water.Use the water and the amide group solvent of any amount all to be considered within the scope of the invention.
Reaction can be carried out being higher than under about 60 ℃ any temperature.Owing to can use the mixed solvent of multiple amido solvent and water, therefore temperature limitation is not geared to actual circumstances a definite upper limit, because temperature is different and different with the ratio of solvent of selecting and selected solvent.
I (a) or II (a) family metal halide open loop epoxide obtain acyl cyanide.Acyl cyanide is hydrolyzed to acid in the presence of water.Can form insoluble carboxylic salt by about 2 equivalents of adding in reaction vessel or more highly basic, rather than separated free acid.This alkali forms two kinds of salt, and a kind of salt of hexahydrobenzoic acid and the salt of a kind of HCN, HCN are to discharge in the hydrolysis of acyl cyanide base.The metal cyanides that produces is dissolved in solvent, and the salt of paraffinic acid is precipitated out from solution.Can except that desolvating paraffinic acid be separated with cyanide salt by simple like this.The present invention can use and be less than 2 normal alkali and carry out, but this might cause the paraffinic acid loss, so this part paraffinic acid can not be precipitated out from solution, and on economic point of view, this is disadvantageous.Unreacted HCN may pollute the paraffinic acid that is precipitated out from solution.Therefore, preferred scheme is to use 2 equivalents or how normal paraffinic acid.
Highly basic of the present invention be can with the salifiable any ion of cryanide ion shape.Can use any strong to the alkali that is enough to form this class salt; The formation of cyanide salt be in confirming this step, whether use have more in two standards of specific alkali decisive.Inorganic hydroxide is preferred.For example, can use lithium hydroxide, sodium hydroxide and potassium hydroxide.Also can use ammonium salt, for example tetraalkylammonium hydroxides or ammonium hydroxide.Lithium hydroxide is preferred, because cyaniding lithium salts height is dissolved in aqueous no proton dipole amide group solvent, when removing the amide group solvent, can more effective and fully remove cryanide ion from hydrochlorate like this.Lithium cyanide more is soluble among the DMF than sodium cyanide or potassium cyanide.Therefore in the salify step, be more favourable as the positively charged ion in the highly basic with lithium.
Preferred version of the present invention is that solvent is packed in the reaction vessel, adds lithiumbromide, adds epoxide then.In case reaction is finished basically, adds two equivalents or how normal lithium hydroxide aqueous solution, hexahydrobenzoic acid salt is filtered out from precipitation, discard solvent.If desired, the lithium salts of hexahydrobenzoic acid can be further purified except that remaining impurities such as cyanide salt, perhaps by with the dissolving of this salt or be suspended in the solvent and make its acidifying be converted into free acid.
The representative reactions route of this method is shown in figure I and figure II.These figure illustrate general method of the present invention with concrete case representation.
Figure I
Figure C9881003000101
Figure C9881003000121
The adoptable second kind of closely similar condition of figure II explanation the present invention.The flow process of this figure is identical with the generalized flow process of figure I, but some conditions of some step change to some extent.
Figure C9881003000122
Figure C9881003000131
It is that the common autre action pendante U. S. application of USSN 60/061613 (on February 12nd, 1997) and the application number that specifies the U.S. are that PCT/US98/02749, publication number are the PCT application of WO 98/34584 that the chemical reaction that figure I describes is recorded in registration number.These applications all are introduced into herein for your guidance, and they are especially relevant with the chemical reaction in 1-7 step.
The chemical reaction of figure II is recorded in the PCT application that the application number of submitting on August 26th, 1998 is PCT/EP98/05504, and it is designated state that this application specifies the U.S..Whole disclosures of this application are incorporated herein by reference.Specifically describe the chemical reaction of figure II below.
The general description of chemical reaction is as follows among figure I and the II:
Under about 125 ℃, cyclopentyl chlorine and Vanillin and the mixture of salt of wormwood in dimethyl formamide stirred be completed into cyclopentyloxy product (about 2 hours) until thinking.This mixture is cooled to 20-25 ℃, removes and with discarding after the methanol wash solid (Repone K and saleratus) is centrifugal.Dimethyl formamide mother liquor and the merging of methanol wash liquid are used for the step down.
The solution of cyclopentyloxy compound in dimethyl formamide and methyl alcohol is cooled to about 0 ℃ and handle (about 1.5 hours) with sodium borohydride.Make temperature remain below 5 ℃.This mixture was stirred 30 minutes at 0-10 ℃, then 25-30 ℃ of stirring until thinking reduction reaction (about 1 hour) fully.Add acetate 50% to consume excessive hydroborate, dimethyl formamide and methyl alcohol are removed in vacuum distilling.After mixture is cooled to 20-25 ℃, be assigned in water and the toluene.The toluene that contains alcohol is with the softening water washing, by being used for the next step behind the strainer.
Under 15-25 ℃, the toluene solution of alcohol is handled with concentrated hydrochloric acid (minimum 36%).The organic phase of chlorine-containing compound separated and with sodium bicarbonate handle with in and trace hydrochloric acid.Solids removed by filtration (sodium-chlor, sodium bicarbonate).
Muriatic solution concentrates through vacuum distilling.After being cooled to about 20 ℃, add softening water, Tetrabutyl amonium bromide and sodium cyanide.After this mixture heating up to 80 ℃, under this temperature, stir until thinking that cyanogenation carries out fully (about 2 hours).
After mixture is cooled to be lower than 60 ℃, it is assigned in water and the toluene.Under 30-25 ℃, the toluene of cyano-containing compound with the softening water washing, is atmospherically distilled to minimum volume, toward wherein adding acetonitrile.The acetonitrile solution of this product can be directly used in down the step.
The acetonitrile solution of preparation methyl acrylate and the solution of triton b (TritonB) and acetonitrile.Be lower than under 25 ℃, the methyl acrylate solution with about 16.6% is added in the cyano compound solution.Add about 12.5% triton b solution, behind this mixture restir number minute, be cooled to and be lower than 25 ℃.More than this interpolation order triplicate, add last 33% methyl acrylate solution and last 50% triton b solution more in two batches.Reaction mixture is stirred react completely until thinking (about 2-3 hour) down at 20-25 ℃.Be atmospherically distilled to minimum volume and remove acetonitrile.Under 50 ℃, this mixture is assigned in hexanaphthene/toluene and the water.Under about 0 ℃, make about 1 hour of the hexanaphthene/toluene phase ageing that contains pimelate.
With the product centrifugation and with cold (being lower than 0 ℃) hexanaphthene/toluene wash.Under the highest 50 ℃, make wet filter cake vacuum-drying, obtain the pimelate of near-white to the cream-coloured powder shape.
The methanol solution of 29% sodium methylate is added in the pimelate De dioxane solution once.With this mixture heating up to about 75 ℃ (backflows) and make it under this temperature, keep all forming (about 1 hour) until 2-methoxycarbonyl hexanaphthene-1-ketone.After distilling most of methyl alcohol, the Yong diox replaces methyl alcohol.In this mixture, add sodium bicarbonate and softening water, be heated to backflow (about 85-88 ℃) and make mixture under this temperature, keep all forming (about 10 hours) until hexanaphthene-1-ketone.
With mixture be cooled to be lower than 60 ℃ after, add concentrated hydrochloric acid solution and make pH reduce to 7.5 by being higher than 10.
Most of diox and methyl alcohol are removed in vacuum distilling.Afterwards, under about 70 ℃, this mixture is assigned in hexanaphthene/toluene and the water.Under about 70 ℃, contain the organic phase softening water washed twice of ketone.
Product solution is cooled to 10 ℃ and about 1 hour of 9-11 ℃ of following ageing.With the product filtering separation and with cold (10 ℃) hexanaphthene/toluene wash,,, obtain the pulverous ketone of near-white with wet cake vacuum-drying being no more than under 50 ℃.
In the presence of mineral alkali and catalytic amount benzyltriethylammoinium chloride (BTEAC), can prepare dintrile (dicarbonitrile) by ketone with chloro acetonitrile treatment ketone.At low temperatures, for example about about 0 ℃, ketone and excessive slightly chloromethyl cyanide in suitable solvent, are added to highly basic (potassium hydroxide aqueous solution) and BTEAC and water-miscible solvent as the mixed solution among the THF, in the mixture in the tetrahydrofuran (THF).During reaction (be generally about 1 hour), reaction remained under this temperature carry out.Separated product, or use this product with the crude product oil form.
With I (a) or II (a) family metal halide dintrile is converted into naphthenic acid.This reaction is following to be carried out: add solvent in container, can enumerate DMF, acetonitrile and water and I (a) or II (a) family metal halide (preferred about 1.5 equivalents), for example LiBr at this; Rare gas element is fed this container; The mixture that adds dintrile A or B or A and B; With container and wherein content about 100 ℃ the heating a few hours, for example 8 hours.Reactant dilutes with DMF and optional water.Add lithium hydroxide aqueous solution (about 50% molar excess is preferred).Suspension forms.(40-80 ℃) stir about is about 1 hour under the temperature that raises slightly.Reclaim lithium salts with ordinary method.
For example, by lithium salts is suspended in organic solvent, in ethyl acetate, handle this suspension with inorganic aqueous acid and prepare acid.Remove organic solvent then, washing also concentrates.Use the ordinary method separated product.
Illustrate rather than limit concrete scheme of the present invention with the following example.The present inventor keeps the scope of illustrating in the appended claims.
Embodiment 1
The preparation of 3-cyclopentyloxy-4-methoxybenzaldehyde
Under 120-125 ℃, with cyclopentyl chlorine (8.48g, 0.08mol), isovanillin (6.12g, 0.04mol) and salt of wormwood (1.1g, 0.08mol) mixture in dimethyl formamide (4.04g) stirred 1.5 hours in reactor (100ml).Sampling is to identify conversion situation in batches.Result (GC): 0.5 area % isovanillin (target :≤1.0 area %).This mixture is cooled to 20 ℃ and solids removed by filtration (saleratus, Repone K).The wet cake methanol wash.
Embodiment 2
The preparation of 3-cyclopentyloxy-4-methoxyl group benzylalcohol
Dimethyl formamide mother liquor that embodiment 1 is obtained and methanol wash liquid merge and transfer in the reactor of cleaning.Add methyl alcohol (8.52g) again and make this batch materials be cooled to 0 ℃.Remain under 4-9 ℃ in temperature, with added on a small quantity more than 10 minutes in 1 hour repeatedly sodium borohydride (0.49g, 0.0129mol).Reactant was stirred 30 minutes at 7.2-10 ℃, be heated to 25 ℃ then.25-31 ℃ stir 110 minutes after, take a sample and analyze (GC), think that reaction is complete.In reactor, add acetate 50% (1.80g) to consume remaining sodium borohydride.In the operation temperature is remained on 24-25 ℃.Dimethyl formamide and methyl alcohol (distillation end point: 58 ℃, 6 millibars) are removed in vacuum distilling.After being cooled to 20-25 ℃, mixture is assigned in water (3.13g) and the toluene (28.07g).Toluene phase (containing title compound) is washed with softening water (2.65g).
Embodiment 3
The preparation of 4-chloromethyl-2-cyclopentyloxy-1-anisole
The toluene solution of embodiment 2 is cooled to 20 ℃, adds concentrated hydrochloric acid (37.5%; 9.80g), during make temperature remain on 20-22.7 ℃.Added after 40 minutes sampling and analyzed (GC), thought that reaction is complete.Be separated and discard the water of bottom.In reactor, add sodium bicarbonate (1.20g) with neutralization residue hydrochloric acid.Stir after 15 minutes, mixture is cooled to 23 ℃, solids removed by filtration (sodium bicarbonate, sodium-chlor).Part toluene (17.07g) is removed in vacuum distilling (distillation end point: 28 ℃, 7 millibars).
Embodiment 4
The preparation of 4-cyanogen methyl-2-cyclopentyloxy-1-anisole
The solution that embodiment 3 is obtained is cooled to and is lower than 25 ℃, add Tetrabutyl amonium bromide (0.205g, 0.63mol), softening water (2.775g) and sodium cyanide (1.976g, 0.039mol), and, stirred 1 hour 50 minutes at 78.1-80.4 ℃ then this mixture heating up to 80 ℃.Sampling is to confirm the conversion of reactant.
Add toluene (5.841g) and softening water (8.76g), be separated (at about 54 ℃) and discard lower aqueous.Toluene phase (containing product) is washed with softening water (13.32g).Toluene is removed in vacuum distilling (distillation end point: 55 ℃, 1 millibar).
Embodiment 5
The preparation of 4-cyano group-4-(3-cyclopentyloxy-4-p-methoxy-phenyl) NSC 52563
At room temperature, the cyanomethylation compound (9.05g of purity 85.4% that embodiment 4 is prepared; The 7.73g of purity 100%; 0.0334mol) be added in the reactor (0.5L).Acetonitrile (28.56g) and softening water (0.07g) are added in this reactor.Preparation methyl acrylate (6.88g, acetonitrile (4.06g) solution of (4.02g) solution of acetonitrile 0.029mol) and methyl alcohol Triton B (40.2%, 50.94g, 2.269molTriton B).Under 20 ℃, add first methyl acrylate solution (1.81g) of about 16.6%.Add first Triton B solution (0.63kg) of about 12.5% then.Temperature after the interpolation is 31 ℃.Under 28 ℃, add second batch about 16.6% methyl acrylate solution (1.82g).The Triton B solution (0.63g) that adds second batch about 12.5% then.Temperature of charge after the interpolation is 36 ℃.Under 35 ℃, add the 3rd batch about 16.6% methyl acrylate solution (1.81g).The Triton B solution (0.62g) that adds the 3rd batch about 12.5% then.Temperature of charge after the interpolation is 32 ℃.Under 32 ℃, add the 4th batch about 16.6% methyl acrylate solution (1.81g).Add about 12.5% Triton B solution (0.63g) then.Temperature of charge after the interpolation is 36 ℃.Under 34 ℃, add the 5th batch about 33.2% methyl acrylate solution (3.64g).The Triton B solution (1.25g) that adds the 5th batch about 25% then.Temperature of charge after the interpolation is 38 ℃.The Triton B solution (1.25g) that adds last batch of about 25% then.Temperature of charge after the interpolation is 36 ℃.Reaction mixture was stirred 1.5 hours at 20-25 ℃.Acetonitrile is removed in vacuum distilling (distillation end point: 59 ℃, 20 millibars).This mixture is assigned in hexanaphthene/toluene (1145.9/254.6g) and the water (559.8g) then.Under 50-52 ℃, hexanaphthene/toluene phase (containing product) is washed with softening water (559.8g).For making the title product crystallization, made product solution be cooled to 0 ℃ with 50 minutes.Inoculate the pimelate crystal seed then and-1-1 ℃ ageing 1 hour.Leach pimelate, reclaim with hexanaphthene/toluene (6.51g/1.44g) washing and with ordinary method.
Embodiment 6
The preparation of 4-cyano group-4-(3-cyclopentyloxy-4-p-methoxy-phenyl) hexanaphthene-1-ketone
(76.52g 1.8112mol) is added in the reactor (100ml) pimelate that embodiment 5 is prepared.The methanol solution of adding diox (2214g) and 29.1% sodium methylate (0.44g, 24mmol).This mixture heating up was stirred 1 hour to backflow (77 ℃) and under this temperature.Sampling is to confirm the conversion of reactant.Distillation for removing methanol (16.82g overhead product) to reactor bottom temperature is 97 ℃.Add fresh De diox (121.6g) and during replenishing distillation, lose the De diox.Add sodium bicarbonate (22.2g, 26.mmol) and softening water (2.47g).This mixture heating up was stirred 10 hours down to backflow (87 ℃) and at about 87 ℃.Sampling is to confirm the conversion of reactant.Reactant is cooled to 78 ℃.Add diox (0.13g) and softening water (0.12g) so that reactant flushes.Be cooled to be lower than 60 ℃ after, add concentrated hydrochloric acid (37%, 0.265g) to adjust pH to 7.5.Diox, methyl alcohol and portion water (27.73g overhead product) are removed in vacuum distilling (distillation end point: 66 ℃, 305 millibars).
Stir down, hexanaphthene (180.0g) and toluene (65.5g) are added in the reactor.Reactant is heated to 70 ℃ and be separated aqueous phase discarded under 70 ℃ or low slightly temperature.Under about 70 ℃, the organic phase that will contain title ketone is washed with two parts of softening waters (amounting to 169.4g).In reactor, add hexanaphthene (165.0g) so that reactant flushes.For making the product crystallization, with making reactant be cooled to 10 ℃ more than 1 hour.Then 9-11 ℃ of ageing 6 hours so that crystallization is complete.Product is filtered and wash with hexanaphthene/toluene (81.5g/27.2g).
Embodiment 7
Suitable-6-[3-(cyclopentyloxy)-4-p-methoxy-phenyl]-1-oxa-volution [2.5] octane- 2, the preparation of 6-dintrile
Flask feeds nitrogen purge at the bottom of the upper end being equipped with the 500ml garden of agitator, internal thermometer.Add 50% potassium hydroxide aqueous solution (22.0g) and tetrahydrofuran (THF) (55.0ml) in the flask.Under stirring at room, add benzyltriethylammoinium chloride (0.81g, 35mmol, 0.05 equivalent).Make this solution be cooled to 0 ℃.At room temperature, in isobaric feed hopper, add the solution that contains tetrahydrofuran (THF) (55.0ml), 4-cyano group-4-(3-cyclopentyloxy-4-p-methoxy-phenyl) hexanaphthene-1-ketone (23.0g, 73mmol, 1.0 equivalents) and chloromethyl cyanide (5.9g, 78mmol, 1.07 equivalents).With flask contents under 0 ℃ of stirring, with the solution that added in the isobaric feed hopper in 15 minutes.Make temperature of reaction remain on 0-5 ℃ and stirred 1 hour.Reactant is warming to 25 ℃, water (90.0ml) and ethyl acetate (90.0ml) dilution.Stirred solution also placed them 30 minutes.Layering separates organic layer and vacuum concentration and obtains resistates.Add methylcyclohexane/THF (5: 1) (54.0ml), this solution is heated to 60 ℃, be cooled to 20 ℃ more than 90 minutes more then; Product begins crystallization in the time of about 40 ℃.Then this suspension is cooled to 0 ℃ and kept 2 hours at 0-5 ℃.Under 0 ℃, product is filtered and wash with methyl alcohol mixed liquor (46.0ml).Desciccate obtains the title product of white crystalline solid shape.
Embodiment 8
Suitable-4-cyano group-4-(3-cyclopentyloxy-4-p-methoxy-phenyl)-
γ-1-hexahydrobenzoic acid lithium, 2 preparation
Figure C9881003000181
Be equipped with toward the upper end that links to each other with caustic scrubber add in the flask at the bottom of the 1.0L three neck gardens of agitator, internal thermometer and reflux exchanger dimethyl formamide (200ml), acetonitrile (200ml), lithiumbromide (32.4g.0.37mol) and water (5.6g, 0.31mol).Stir this suspension until obtaining solution, add suitable-6-[3-(cyclopentyloxy)-4-p-methoxy-phenyl afterwards]-1-oxa-volution [2.5] octane-2, the 6-dintrile, 1 (90.0g, 0.25mol).Reactant in the flask was heated 8-12 hour down at 90-95 ℃.Reactant is cooled to 60 ℃ also with dimethyl formamide (270ml) dilution.In this amber solution (60 ℃), add lithium hydroxide aqueous solution (21.65g, 0.51mol one hydronium(ion) oxidation lithium is dissolved in the 112.5ml water) fast.This suspension stirred 1 hour at 60 ℃, was cooled to 5 ℃, and kept 1 hour at 5 ℃.With this suspension filtered, wash the line space air dry of going forward side by side with ethyl acetate (100ml), obtain 2 with 79.5% calibration productive rate.
Embodiment 9
Suitable-4-cyano group-4-(3-cyclopentyloxy-4-p-methoxy-phenyl)-γ-1-hexahydrobenzoic acid, 3
Preparation
Figure C9881003000191
Be equipped with toward the upper end at the bottom of the 1.0L three neck gardens of agitator and internal thermometer and add suitable-4-cyano group-4-(3-cyclopentyloxy-4-p-methoxy-phenyl)-γ-1-hexahydrobenzoic acid lithium in the flask, 2 (58.5g, 0.167mol) and ethyl acetate (500ml).In this light suspension fluid of stirring at room, add then the 3N aqueous hydrochloric acid (70ml, 0.21mol).The reactant stirring was transferred in the separating funnel after 10 minutes.Separate organic phase and wash once (100ml) with water.Separate organic layer and be filtered to being equipped with at the bottom of the 1.0L three neck gardens that still head and upper end be equipped with agitator in the flask of cleaning.Steam and remove ethyl acetate (200ml) concentration response thing.Enriched material in the flask is cooled to 60 ℃, adds heptane (275ml) then.This suspension is cooled to 5 ℃ and kept 2 hours at 5 ℃, filters and wash with cold (5 ℃) heptane (50ml).Product is dried to weight in vacuum chamber, obtain 50.0g (85%) 3

Claims (7)

1, the method for preparation formula (I) compound,
Figure C988100300002C1
Wherein
R 1Be-(CR 4R 5) rR 6, wherein moieties can randomly be replaced by one or more halogens;
R is 0 to 6;
R 4And R 5Be independently selected from hydrogen or C 1-2Alkyl;
R 6Be C 3-6Cycloalkyl or comprise the C of one or two unsaturated link(age) 4-6Cycloalkyl, cycloalkyl wherein and heterocyclic moiety can randomly be replaced by 1 to 3 methyl or an ethyl;
X is YR 2, halogen, nitro, NH 2Or methane amide;
X 2Be O;
Y is O;
R 2Be independently selected from randomly by one or more halogens replace-CH 3Or-CH 2CH 3
R 3Be hydrogen, halogen, C 1-4Alkyl, CH 2NHC (O) C (O) NH 2, the C that replaces of halogen 1-4Alkyl ,-CH=CR 8' R 8', randomly by R 8 'The cyclopropyl, CN, the OR that replace 8, CH 2OR 8, NR 8R 10, CH 2NR 8R 10, C (Z ') H, C (O) OR 8, C (O) NR 8R 10Or C ≡ CR 8';
R 8Be hydrogen or the C that randomly replaced by one to three fluorine 1-4Alkyl;
R 8 'Be R 8Or fluorine;
R 10Be OR 8Or R 11
R 11Be hydrogen or the C that randomly replaced by one to three fluorine 1-4Alkyl;
Z ' is O, NR 9, NOR 8, NCN, C (CN) 2, CR 8CN, CR 8NO 2, CR 8C (O) OR 8, CR 8C (O) NR 8R 8, C (CN) NO 2, C (CN) C (O) OR 9Or C (CN) C (O) NR 8R 8
R ' and R " be independently selected from hydrogen or-C (O) OX, wherein X is hydrogen or Li;
This method comprises:
A) with the compound of lithiumbromide or magnesium bromide halogenide and a kind of no proton dipole amide group solvent and water and formula II (a) or II (b),
Figure C988100300003C1
Among formula II (a) and the II (b), R 1, R 3, X 2Has identical meanings in the formula (I) with X;
B) with described mixture at least about 60 ℃ the heating a few hours, this heating can be chosen wantonly under inert atmosphere and carry out;
C) add capacity LiOH in the described mixture and be settled out formula (I) compound, X is formula (I) compound of Li among C (O) OX to form;
D) from described precipitation, remove amide group solvent and water, and randomly
1) be further purified described Li salt, or
2) make the acidifying of described Li salt, obtain free acid.
2, the process of claim 1 wherein R in the formula (I) 1Be-CH 2-cyclopropyl, cyclopentyl, 3-hydroxycyclopent base, methyl or CF 2H; X is YR 2Y is an oxygen; X 2Be oxygen; And R 2Be CF 2H or methyl; And R 3Be CN.
3, the method for claim 2, first proton dipole amide group solvent wherein is dimethyl formamide, N,N-DIMETHYLACETAMIDE or N-Methyl pyrrolidone.
4, the method for claim 3, halogenide wherein are that lithiumbromide and amide group solvent are dimethyl formamides.
5, the method for claim 4, wherein the amount of water accounts in the reaction vessel more than the content weight 0.1 weight %.
6, the method for claim 5, the compound of formula II wherein (a) or II (b) is suitable-6-[3-(cyclopentyloxy)-4-p-methoxy-phenyl]-1-oxa-volution [2.5] octane-2, the 6-dintrile.
7, a kind of compound, it is suitable-4-cyano group-4-(3-cyclopentyloxy-4-p-methoxy-phenyl)-γ-1-hexahydrobenzoic acid lithium.
CNB988100304A 1997-10-10 1998-10-07 Method for preparing substituted 4-phenyl-4-cyanocyclohexanoic acids Expired - Fee Related CN1192025C (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US6161397P 1997-10-10 1997-10-10
US60/061,613 1997-10-10

Publications (2)

Publication Number Publication Date
CN1275052A CN1275052A (en) 2000-11-29
CN1192025C true CN1192025C (en) 2005-03-09

Family

ID=22036929

Family Applications (1)

Application Number Title Priority Date Filing Date
CNB988100304A Expired - Fee Related CN1192025C (en) 1997-10-10 1998-10-07 Method for preparing substituted 4-phenyl-4-cyanocyclohexanoic acids

Country Status (30)

Country Link
EP (1) EP1043930A4 (en)
JP (1) JP2001519363A (en)
KR (1) KR100560038B1 (en)
CN (1) CN1192025C (en)
AP (1) AP1335A (en)
AR (1) AR015952A1 (en)
AU (1) AU741832B2 (en)
BG (1) BG104302A (en)
BR (1) BR9814064A (en)
CA (1) CA2305614A1 (en)
DZ (1) DZ2619A1 (en)
EA (1) EA003609B1 (en)
HU (1) HUP0003905A3 (en)
ID (1) ID25536A (en)
IL (1) IL135434A (en)
MA (1) MA24670A1 (en)
MY (1) MY122105A (en)
NO (1) NO20001777L (en)
NZ (1) NZ503759A (en)
OA (1) OA11347A (en)
PE (1) PE121599A1 (en)
PL (1) PL191974B1 (en)
SA (1) SA99191000A (en)
SK (1) SK4902000A3 (en)
TR (1) TR200000945T2 (en)
TW (1) TW440557B (en)
UA (1) UA67753C2 (en)
UY (2) UY25201A1 (en)
WO (1) WO1999018793A1 (en)
ZA (1) ZA989228B (en)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9920152D0 (en) * 1999-08-25 1999-10-27 Smithkline Beecham Plc Novel process
JP2003534238A (en) * 1999-12-15 2003-11-18 スミスクライン・ビーチャム・コーポレイション Salt of cis-4-cyano-4- [3- (cyclopentyloxy) -4-methoxyphenyl] cyclohexane-1-carboxylic acid.
KR20020073183A (en) * 2000-01-26 2002-09-19 스미스클라인 비참 코포레이션 Monohydrate of Cis-Lithium-Cyano-4-[3-(Cyclopentyloxy)-4-Methoxyphenyl]Cyclohexanecarboxylate
EP2258689A1 (en) 2000-03-16 2010-12-08 Biolipox AB Benzylated PDE4 inhibitors
US7250518B2 (en) 2001-01-31 2007-07-31 Pfizer Inc. Nicotinamide acids, amides, and their mimetics active as inhibitors of PDE4 isozymes
CA2436535A1 (en) 2001-01-31 2002-08-08 Prizer Products Inc. Nicotinamide biaryl derivatives useful as inhibitors of pde4 isozymes
DE60113731T2 (en) 2001-01-31 2006-06-29 Pfizer Products Inc., Groton ETHER DERIVATIVES SUITABLE AS INHIBITORS OF PDE4 ISOZYME
KR20030072614A (en) 2001-01-31 2003-09-15 화이자 프로덕츠 인크. Thiazolyl-, Oxazolyl-, Pyrrolyl-, and Imidazolyl-Acid Amide Derivatives Useful as Inhibitors of PDE4 Isozymes
CN102491959B (en) * 2011-12-19 2015-03-25 江苏澄扬作物科技有限公司 Preparation method of oxirane derivative

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4021478A (en) * 1972-07-13 1977-05-03 The Upjohn Company Preparation of carboxylic acids from glycidonitriles with ionic lewis acids
SK279958B6 (en) * 1992-04-02 1999-06-11 Smithkline Beecham Corporation Compounds exhibiting anti-allergic and anti-inflammatory properties, pharmaceutical composition them containing and their use
US5524438A (en) * 1994-12-15 1996-06-11 United Technologies Corporation Segmented bulkhead liner for a gas turbine combustor
MY118813A (en) * 1997-02-12 2005-01-31 Smithkline Beecham Corp Compounds and method for preparing substituted 4-phenyl-4-cyanocyclohexanoic acids
US6452022B1 (en) * 1997-10-10 2002-09-17 Smithkline Beecham Corporation Method for preparing substituted 4-phenyl-4-cyanocyclohexanoic acids

Also Published As

Publication number Publication date
TW440557B (en) 2001-06-16
AP1335A (en) 2004-11-29
PL191974B1 (en) 2006-07-31
MA24670A1 (en) 1999-07-01
OA11347A (en) 2003-12-17
SK4902000A3 (en) 2000-11-07
KR20010015709A (en) 2001-02-26
UA67753C2 (en) 2004-07-15
ID25536A (en) 2000-10-12
EP1043930A1 (en) 2000-10-18
IL135434A0 (en) 2001-05-20
TR200000945T2 (en) 2000-10-23
EP1043930A4 (en) 2004-09-15
PE121599A1 (en) 2000-02-19
AR015952A1 (en) 2001-05-30
UY25201A1 (en) 2001-08-27
AU9687498A (en) 1999-05-03
HUP0003905A2 (en) 2001-03-28
JP2001519363A (en) 2001-10-23
EA003609B1 (en) 2003-06-26
WO1999018793A1 (en) 1999-04-22
UY25524A1 (en) 2000-02-23
AU741832B2 (en) 2001-12-13
MY122105A (en) 2006-03-31
DZ2619A1 (en) 2003-03-08
CA2305614A1 (en) 1999-04-22
NO20001777L (en) 2000-05-03
PL339759A1 (en) 2001-01-02
ZA989228B (en) 1999-04-12
BG104302A (en) 2001-08-31
SA99191000A (en) 2005-12-03
CN1275052A (en) 2000-11-29
EA200000406A1 (en) 2000-10-30
KR100560038B1 (en) 2006-03-13
HUP0003905A3 (en) 2002-01-28
BR9814064A (en) 2000-09-26
IL135434A (en) 2004-12-15
NO20001777D0 (en) 2000-04-06
AP2000001782A0 (en) 2000-06-30
NZ503759A (en) 2002-03-01

Similar Documents

Publication Publication Date Title
CN1149190C (en) Nitric oxide synthase inhibitors
CN1527814A (en) Nitric oxide synthase inhibitor phosphate salt
CN1845917A (en) 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridine-2-yl-amino]-propionic acid ethyl ester methane sulphonate and use thereof as a medicam
CN101039917A (en) Process for preparing telmisartan
CN1426396A (en) Substituted benzoic acid amides and use for inhibition of angiogenesis thereof
CN1192025C (en) Method for preparing substituted 4-phenyl-4-cyanocyclohexanoic acids
CN1198799C (en) Crystalline form of (S)-2-ethoxy-3-[4-(2-{4-methane sulfonyloxy phenyl} ethoxy) phenyl] propanoic acid
CN1551879A (en) Stable polymorph of FLIBANSERIN, technical process for its preparation and the use thereof for preparing medicaments
CN1015256B (en) Process for preparing substituting compounds of benzyl butenyl amido
CN1080289A (en) 3- (1H-tetrazol-5-yl) -4H-pyrido [1, 2-a ] pyrimidin-4-ones, pharmaceutical compositions containing them and process for their preparation
CN1874998A (en) 1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-yl]-methyl piperidine oxalate (donepezil oxalate) and its polymorphs
CN1027259C (en) Improved process for preparation of 3,5,6-trichloropyridin-2-01
CN1227538A (en) Pharmaceutical composition containing 4-oxo-butynic acid
CN1009826B (en) The method for preparing quinoline compound
CN85101426A (en) The preparation method of two of optically-active-(3-chloro-2-oxygen-oxypropyl trimethyl ammonium)-tartrate
CN1040976A (en) The preparation method of the beta-diketon that replaces
CN1498216A (en) Noval crystal and solvate forms of ondansetron hydrochloride and process for their preparation
CN1307563A (en) N-phenyl-N'-phenylpropylpiperazine derivatives and process for the preparation thereof
CN1301982C (en) Compounds and method for preparing substituted 4-phenyl-4-cyanocyclohexanoic acids
CN1198735A (en) Benzenesulphonamide derivatives, preparation thereof and therapeutical uses thereof
CN1053895C (en) Novel substituted sulphonic acid amide, preparation and pharmaceutical composition of same
CN1030077A (en) Famotidine pyridine polymorphic form and preparation method thereof
CN1080265C (en) Process for preparation of 7-alkoxyalkyl-1,2,4-triazolo (1,5-A) pyrimidine derivatives
CN1882526A (en) Process for the preparation of voglibose
CN1395555A (en) Calcium dicarboxylate ethers, method of making same, and treatment of vascular disease and diabetes therewith

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
C17 Cessation of patent right
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20050309

Termination date: 20101007