Specific electron transporting molecules that can be prepared in accordance with the present invention are selected from the group consisting of anthrone derivatives and anthraquinodimethane derivatives of the following formulas: wherein A and B are independently selected from the group consisting of CN and COOR, wherein R is an alkyl group or an aryl group; X and Y are independently selected from the group consisting of alkyl, aryl, halide, hydroxy and electron withdrawing groups such as CN, NO 2 , COR, COOR, and the like, wherein R is as defined herein, and m and n are numbers of from 0 to 3.

With further reference to the process of the present invention, the condensation reaction of the anthraquinone with active methylene compounds, inclusive of malononitrile, (dicyanomethane), malonate (bis[methoxycarbonyl]methane), dinitromethane, beta diketones, and the like, is affected in a suitable organic solvent at room temperature in the presence of a base and a Lewis acid. With the proper choice of reactants, both the 11,11,12,12-tetrasubstituted anthraquinodimethane and 10-disubstituted methylene anthrone derivatives can be obtained by similar synthetic process.

More specifically, the electron transporting anthrone Pharmaceutical Intermediates   derivatives are prepared by reacting 1 mole of an anthraquinone with 1 to 1.5 moles of an active methylene compound. The aforementioned condensation is affected in the presence of an excess, generally 2 to 5 moles, of a Lewis acid such as titanium tetrachloride and an excess, generally 4 to 20 moles, of a base inclusive of pyridine. Suitable solvents for the reaction include chlorinated compounds like methylene chloride, chloroform, and 1,2-dichloroethane; and ethyl acetate. Also, this reaction is usually initially accomplished at ice-bath temperatures, and then at room temperature.

Therefore, the preparation of anthrone derivatives, which can be purified by recrystallization or by chromatography, and are characterized by elemental analysis, spectroscopy and mass spectrometry, can be illustrated with reference to the following reaction scheme:  wherein X, Y, Z, m and n are as defined hereinbefore.

Similarly, the electron transporting anthraquinodimethane derivatives are synthesized by reacting 1 mole of an anthraquinone with 2 to 3 moles of an active methylene compounds such as malonoitrile, malonate, and the like. The aforementioned condensation is affected in the same manner with reference to the preparation of the anthrone manufacturer derivatives except that additional Lewis acid and base are employed. Generally, thus for each mole of anthraquinone, 3 to 5 moles of titanium tetrachloride, and 6 to 25 moles of pyridine were used.

Accordingly, the preparation of anthraquinodimethane derivatives, which can be purified by simple recrystallization from a suitable solvent or by chromatography, and are characterized by elemental analysis, standard spectroscopic and mass spectrometric techniques, can be illustrated by the following reaction sequence: wherein X, Y, A, m and n are as defined herein.

With further reference to the synthesis of the anthraquinodimethane derivatives with different substituents, that is, wherein the A substituent, for example, is CN, and the B substituents are COOR, at the carbon-11 and carbon-12 position, there is reacted 10-disubstituted methylene anthrones , with 1 to 1.5 moles of active methylene compounds, in accordance with the following reaction scheme (III). The aforementioned condensation is affected in the presence of an excess, generally 2 to 5 moles of a Lewis acid such as titanium tetrachloride, and an excess, generally 4 to 20 moles, of a base inclusive of pyridine. Suitable solvents for this reaction include chlorinated compounds like methylene chloride, chloroform, and 1,2-dichloroethane; and ethylacetate. Also, this reaction is usually initially accomplished at ice bath temperatures, and then at room temperature.  wherein the A substituents are COOR, the B substituents are CN, and the other substituents are as defined herein.

With regard to all the reactions illustrated herein, the reaction temperature generally ranges from about 0° to about 30° C. Electrical testing was carried out in accordance with the procedure of Example VIII. Specifically, this imaging member was positively charged to fields of 40 volts/micron and exposed to white light of wavelengths of 400 to 700 nanometers. The half decay exposure sensitivity of this device was 50 ergs/cm 2 , and its electrical properties remained substantially the same after 1,000 cycles of repeated charging and discharging.

Other modifications of the present invention may occur to those skilled in the art based upon a reading of the present disclosure and these modifications are intended to be included within the scope of the present invention.

Valuable pyridazinone Pharmaceutical Intermediates   to pharmaceutically useful compounds can be prepared in surprisingly high yields by the quinoline catalyzed reaction of the corresponding monohydrazone with an appropriately substituted acetic acid ester. In an especially preferred embodiment, p,p'-dichlorobenzil monohydrazone and methyl acetoacetate are reacted in a xylene solvent in the presence of quinoline to afford 4-acetyl-5,6-bis(p-chlorophenyl)-2H-pyridazin-3-one, which can then be reacted with ethylene carbonate in the presence of potassium carbonate to afford the antihypertensive agent, 4-acetyl-5,6-bis(p-chlorophenyl)-2-(2'-hydroxyethyl)-2H-pyridazin-3-one.

The present invention provides an improved process for the synthesis of pyridazinones which are valuable intermediates to pharmaceutically useful compounds, said process comprising the quinoline catalyzed reaction of the corresponding monohydrazone with an appropriately substituted acetic acid ester.It is therefore a primary object of the present invention to provide an improved process for the preparation of the antihypertensive agents of formula (I) and Pharmaceutical Intermediates manufacturer thereto. More particularly, it is a primary object of the present invention to provide an improved process for the preparation of compounds of formula (Ia) in substantially higher yields than heretofore possible, thus affording a commercially viable route to the formula (I) antihypertensives.

These and similar objects are accomplished according to the present invention by the quinoline catalyzed reaction of a monohydrazone of formula (II) above with an appropriately substituted acetic acid ester of formula (III) above in a suitable solvent, at elevated temperature, to afford the corresponding compound of formula (Ia). It has surprisingly been found that quinoline is vastly superior to the sodium alkoxide condensing agents typically used in the prior art. Also, quinoline has been found to be a much more effective catalyst than pyridine. Thus, only 20% yields of 4-acetyl-5,6-bis(p-chlorophenyl)-2H-pyridazin-3-one are reported in U.S. Ser. No. 11,416 when using a sodium ethoxide reagent to effect ring closure. Similarly, it has more recently been found that use of pyridine as the condensing agent affords the desired 4-acetyl-5,6-bis(p-chlorophenyl)-2H-pyridazin-3-one in less than 35% yield. In contrast, yields of up to 76% of the aforesaid key intermediate have been obtained when using quinoline to catalyze the reaction. It has also surprisingly been found that, with quinoline, yields of up to 76% are obtained using only half as much catalyst as required in the case of pyridine. In fact, a ratio of 1 g quinoline per 7.1 g monohydrazone (1.0 mole quinoline/3.16 moles monohydrazone) has afforded yields comparable to those obtained with 1 g quinoline/3.5 g monohydrazone, and considerably superior to those obtained with 1 g pyridine/3.4 g monohydrazone.

The condensation of a methyl acetoacetate molecule with p,p'-dichlorobenzil monohydrazone may go in either of two directions, as depicted below. ##STR10## The formation of the desired pyridazinone key Pharmaceutical Intermediates is favored at temperatures above 110° C. The undesired reverse addition product, 3-(4,4'-dichlorobenzilmonoazino)-1-methoxy-1,3-butanedione, is favored at lower temperatures and may even constitute the major reaction product under improper reaction conditions. It is also important that the methanol (and water) by-products be removed from the reaction zone as they are formed. Because the monohydrazone degrades at elevated temperatures, the initial reaction with elimination of the methanol by-product should be carried out rapidly. Presence of p-chlorobenzoic acid, hydrazine or methanol in the monohydrazone feedstock reduces yields. Therefore, the monohydrazone starting material should be of high quality. To obtain the desired degree of purity, the monohydrazone starting material [which has typically been prepared by (1) a classical benzoin condensation in which p-chlorobenzaldehyde in the presence of potassium cyanide is converted to p,p'-dichlorobenzoin in refluxing methanol and water solvents; followed by (2) oxidation of the dichlorobenzoin to the dichlorobenzil using concentrated nitric acid in glacial acetic acid solvent; followed by (3) conversion of the dichlorobenzil to the monohydrazone by reaction with hydrazine hydrate in isopropanol at reflux temperature] is recrystallyzed from isopropanol prior to its use in the cyclization process of the present invention.

U.S. Application Ser. No. 11,416 now U.S. Pat. No. 4,238,490 teaches that the subject pyridazinones, i.e., substituted keto-pyridazine compounds of formula (I), may be prepared by various alternative methods theretofore employed in the synthesis of other pyridazinone compounds (e.g., in U.S. Pat. No. 2,839,532) or modifications thereof to obtain the R 1 , R 7 , X c  or Y c substituents thereon as defined above. In general, one method for the preparation of pyridazin(2H)-3-ones comprises reacting an appropriately substituted monohydrazone, with the appropriately substituted acetic acid ester or reacting the appropriately substituted benzil and appropriately substituted hydrazide under cyclization conditions, e.g., in the presence of suitable solvents, such as xylene, acetonitrile, methanol, benzene, etc., and alkaline condensing agents, such as hydroxides, alcoholates, hydrides, alkali or alkaline earth metals, tertiary amines, etc., to effect ring closure. The foregoing general reaction scheme may be depicted as follows ##STR7## wherein R is typically an alkyl group and R 7  is not here restricted by the provisos set forth earlier. As will be apparent from the foregoing description of the formula (I) substituents, the formula (Ia) products are in some instances pharmacologically active compounds of formula (I), while in other instances the formula (Ia) Pharmaceutical Intermediates products which can be converted by subsequent reactions to the compounds of formula (I).

The monohydrazone reactants may be prepared by the reaction of an appropriate substituted benzil with hydrazine hydrate. Suitable benzil starting materials may be obtained commercially or prepared by known methods, for example, cyanide ion catalyzed benzoin condensation followed by oxidation. The pyridazin(2H)-3-one compounds thus prepared may be utilized following suitable recrystallization/purification as intermediates for the preparation of further 2-substituted derivatives in accordance with the above R 1 definition.

 

 

source:freepatentsonline

In one aspect, the present invention relates to a pharmaceutical composition for subsequent use in the treatment of a sexual dysfunction (SD); the pharmaceutical composition comprising an agent capable of modulating the activity of an Pharmaceutical Intermediates   conductance calcium-activated potassium (IK  Ca  ) channel in the sexual genitalia of an individual; wherein the agent is optionally admixed with a pharmaceutically acceptable carrier, diluent or excipient.

Alternatively expressed, the present invention relates to a pharmaceutical composition for use (or when in use) in the treatment of a sexual dysfunction (SD); the pharmaceutical composition comprising an agent capable of modulating the activity of an intermediate conductance calcium-activated potassium (IK  Ca  ) channel in the sexual genitalia of an individual; wherein the agent is optionally admixed with a pharmaceutically acceptable carrier, diluent or excipient.

Citric acid is a weak organic acid. It is used to add sour taste in the food industry and as a preservative. It is also used in the pharmaceutical industries . Citric acid is an important metabolic intermediate for the conversion of fats and carbohydrates to energy. Therefore, citric acid is naturally occurring in all organisms and is found in large quantities in citrus fruits. It is commercially manufactured by the bacterial fermentation of sugars, particularly by the bacterium Aspergillus niger.

The pharmaceutical compositions may be for human or animal usage in human and veterinary medicine and will typically comprise any one or more of a pharmaceutically acceptable diluent, carrier, or excipient. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985). The choice of pharmaceutical carrier, excipient or diluent can be selected with regard to the intended route of administration and standard pharmaceutical practice. The pharmaceutical manufacturer compositions may comprise as—or in addition to—the carrier, excipient or diluent any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilising agent(s).

Citric acid plays an important role in metabolism. It participates in the tricarboxylic acid cycle (Krebs cycle) and leads to the eventual oxidation of the carbohydrates and fats into carbon dioxide and water. Citrate is one of the metabolic intermediates in the body after carbohydrates undergo glycolysis. The last step of glycolysis results in the production of pyruvate. Pyruvate enters the tricarboxylic acid cycle, which is a series of 10 reactions to generate more energy (either ATP or NADH+) in the cell.

In one aspect, the present invention relates to a pharmaceutical composition for subsequent use in the treatment of a sexual dysfunction (SD); the pharmaceutical composition comprising an agent capable of modulating the activity of an intermediate conductance calcium-activated potassium (IK  Ca  ) channel in the sexual genitalia of an individual; wherein the agent is optionally admixed with a Pharmaceutical Intermediates   acceptable carrier, diluent or excipient and wherein the modulation of the IK  Ca  channel activity is capable of mediating a relaxation of corpus cavernosal smooth muscle tone.

Citric acid has many uses. It is used in the food industry as an additive to impart sour taste to candies, sodas and other foods. Because of its weakly acidic nature, it is an excellent preservative and is often added to preserve vegetables. It is also used in personal care products such as soaps and shampoos.

In another aspect, the present invention relates to a pharmaceutical composition for subsequent use in the treatment of a sexual dysfunction (SD); the pharmaceutical composition comprising an agent capable of modulating the activity of an intermediate conductance calcium-activated potassium (IK  Ca  ) channel in the sexual genitalia of an individual; wherein the agent is optionally admixed with a pharmaceutically acceptable carrier, diluent or excipient and wherein the modulation of the IK  Ca  channel activity is capable of mediating a relaxation of corpus cavernosal smooth muscle tone.

Ferrocene compounds are produced from related intermediates, wherein the ferrocene compounds are represented by the general formula (I): ##STR1## wherein Z is one of the groups --CH2 --Y, --CO--(CH2)n --CO--X or --CO--X, in which n is 1 to 6; X is an (oligo-)alkylene glycol residue with 1 to 10 alkoxy units or an alkanediol residue with 2 to 18 carbon atoms, and Y is X or OH, and

R is an alkyl group with 2 to 18 carbon atoms, an aralkyl group with 7 to 20 carbon atoms, or H, when Y≠OH.

The related intermediates differ from the ferrocene carboxylic acid in that Z is replaced by Z' which is --COOH or --CO--(CH2)n --COOH. The ferrocene compounds of formula (I) are especially suitable as combustion moderators for solid fuels.

Ferrocenyl esters are known from the prior art, such as 2(2-n-butoxyethoxy)ethylferrocene (note U.S. Pat. No. 3,558,680) which can be produced from ferrocenecarboxylic acid and 2-(2-n-butoxyethoxy)ethanol.

Ferrocene derivatives are used as combustion moderators for solid propellants, among other things. Most of the known combustion moderators containing ferrocene derivatives however exhibit the undesirable property of migration. In other words these derivatives migrate out of a rubber-elastic binder matrix of the solid propellant into the surrounding insulating material, resulting in irregular combustion and deterioration of the resistance of the solid propellant to aging.

To solve this problem, relatively Pharmaceutical Intermediates   have been developed which have a significantly reduced or even completely absent migration behavior, for example so-called Butacene® (cf. EP 169 130 and EP 171 307). Apart from the difficult and complex method of manufacture, these derivatives exhibit a poorer combustion when the same amounts are added by comparison with the migrating ferrocene derivatives as combustion moderators.

There have also been developments (for example note U.S. Pat. No. 3,932,240) in which ferrocene derivatives have been incorporated into the plastic matrix of the solid propellant with hydroxyl or isocyanate groups in the terminal positions, by reactions. However, these combustion moderators likewise exhibit unsatisfactory combustion.
One suitable method for manufacturing the ferrocenecarboxylic acid esters according to the invention (Z=--CO--X) is synthesis by means of the respective analogous intermediate with Z'=--COOH. As a rule, a surplus of the corresponding diol or glycol compound is used. Preferably, the excess diol or glycol compound is a multiple of the stoichiometrically necessary amount.

As a result, the conversion of the carboxylic acid starting material is increased and at the same time assurance is provided that only one OH group of the respective diol or glycol reacts. Normally, carboxylic acids generally react only slowly with alcohols because of the low carbonyl activity. By adding catalysts, usually typical esterification catalysts, especially acids, esterification can be accelerated considerably. Preferred catalysts are the organic sulfonic acids especially methanesulfonic acid. By removal of the resultant water of reaction the conversion of the ferrocene carboxylic acid used can be considerably increased.

Completely analogously, the esterification of the intermediates of the general formula (I') with Z'=--CO--(CH 2 ) n --COOH can be performed with the corresponding glycol or diol compounds to produce the ferrocene compounds according to the invention with Z=--CO--(CH 2 ) n --CO--X.

The invention is also directed to the ferrocene derivatives required as intermediates for the manufacture of the ferrocene compounds (I) according to the invention, and their manufacture. These intermediate ferrocene compounds with the general formula (I') are those where Z=--COOH or Z=--CO--(CH 2 ) n --COOH in which n=1 to 6 and R is an alkyl group with 2 to 18 carbon atoms or an aralkyl group with 7 to 20 carbon atoms, preferably an alkyl group with 2 to 4 carbon atoms.

The (Ar-)ferrocene carboxylic acids (Z'=COOH) can be produced by carboxylation of the (Ar-)alkylferrocene. Here (Ar-)alkylferrocene refers to a ferrocene derivative wherein R is the aralkyl group, noted heretofore. Preferably the reaction is performed in an organic solvent saturated with carbon dioxide in the presence of a Lewis acid, especially aluminum chloride.

 

 

from:freepatentsonline

 1 - bromo-ethoxy ethyl carbonate

1 - bromo-ethoxy ethyl carbonate is a cephalosporin antibiotic Cefuroxime Axetil Pharmaceutical Intermediates , Cefuroxime Axetil in 2001 global sales of 470 million U.S. dollars up to now there are more than domestic production. - - Synthesis of the intermediate line of four, 1) from chloride and bromide ethoxy radical reaction to be 1 - bromo-ethoxy chloride, the latter with alcohol for the esterification reaction; 2) diethyl carbonate be directly brominated ester, a by-product of too much of the Act; 3) 1 - chloro-ethoxy carbonate salt with excess bromine substitution reaction, commonly used are lithium bromide salt, lithium tetraethylammonium bromide, tetrabutylammonium bromide lithium and so on; 4) ethyl vinyl carbonate reaction with hydrogen bromide, which does not use solvents, but the yield and selectivity are relatively good.

7 - hydroxy-isoflavone

7 - Hydroxy-isoflavone is a representation of the treatment of osteoporosis new drug intermediates Ipriflavone, Ipriflavone by Takeda of Japan to develop new drugs for Pharmaceutical Intermediates manufacturer . 7 - The main use of synthetic genistein 2,4 - dihydroxyphenyl benzyl ketones with triethyl orthoformate conducted in cyclization catalyst, different patents and solvent catalyst is reported only choice is different from internal research shows that the use of isopropyl alcohol as solvent, morpholine as a catalyst for a good synthetic route, by-products of which 7 - ethoxy-isoflavone low. Synthesis of the key is genistein 2,4 - dihydroxyphenyl benzyl ketone, which can not only synthesis of intermediates 7 - genistein, but also a variety of fine chemical synthesis, there are three synthesis routes, 1) benzene acetonitrile with resorcinol in the condensation of anhydrous ethyl ether, ethyl ether in industrial production as a result of difficult recovery, with domestic researchers 1,2 - dichloroethane in place of ethyl ether, ethylene glycol at the same time by adding a catalyst for dimethyl ether; 2) is phenylacetic acid as a catalyst in the presence of anhydrous zinc chloride with resorcinol reaction, in which acid is a reaction of raw materials is the reaction medium, the better the quality of products; 3) phenylethyl chloride as raw materials for the Lewis acid catalyst , in an inert organic solvent condensation with resorcinol to be 2,4 - dihydroxyphenyl benzyl ketones. Acid method in which the economy, with prospects for development.

Chlorophenyl acetone on

Of acetone chlorophenyl be sympathetic for the synthesis of drugs on amphetamine-chloro important Pharmaceutical Intermediates, in recent years, strong demand for domestic and foreign markets. Benzylcyanide original line is as raw material, in the presence of sodium acetate, to react with ethyl acetate, and then acidified to be, the line emissions from waste, and the high cost of raw materials; in recent years to develop a domestic Chlorobenzyl chloride synthesis process as raw materials, rather development potential. Of chlorine in benzyl chloride as the solvent tetrahydrofuran synthesis and zinc based on zinc chloride solution tetrahydrofuran; add drops of acetic anhydride chlorobenzyl zinc chloride reaction of tetrahydrofuran solution, and then adding sulfuric acid to be on the chlorophenyl acetone. The route is simple, high yield, great developing prospect.

4′-Benzyloxy–3 ‘- nitro acetophenone

4′-Benzyloxy–3 ‘- nitro acetophenone synthetic intermediates formoterol, formoterol is by the Japanese company Yamanouchi new listing of new, long-term β2-adrenergic receptor agonist antiasthmatic drugs, primarily for bronchial asthma, the role of strong and durable. Dihydroxyacetophenone to as raw materials for use nitrate nitrification be 4′-hydroxy -3 ‘- p-ethyl ketone, the latter with potassium carbonate, sodium iodide, benzyl chloride and chloroform mixed-heating reaction, the separation of organic after layer, the concentration after washing and the use of isopropyl ether - butanone recrystallization be 4′-benzyloxy–3 ‘- nitro acetophenone. The first step in nitrification reaction in which temperature control is very important for the general at low temperatures, or else too many easy dinitro compounds; the second reaction phase transfer catalyst can be used, the expectations can get a better yield and product purity.

5 - methoxy-uracil

5 - methoxy-uracil is a pyrimidine synthesis of RNA and DNA pyrimidine important Pharmaceutical generics, nucleotides current anti-virus, anti-cancer substances are the main material, 5 - methoxy-uracil is a type of nucleic acid base uracil the basis of drug intermediates, can be synthesized series of important anti-cancer drug. Synthesis of the main routes, 1) to methyl isothiourea sulfate solution of sodium hydroxide added to α-methoxy-acrylic ester-β-hydroxy-sodium in the reaction suspension, after removal of sodium sulfate, acidified with sulfuric acid get products, the more difficult route of raw materials; 2) methoxy-ethyl acetate and sodium in metal-catalyzed Claisen ester condensation to be sodium salt, and then with the nucleophilic addition of thiourea was 2 — sulfhydryl -4 - hydroxy -5 - methoxy-pyrimidine, after hydrolysis give the 5 - methoxy-uracil, which line is longer, but the source of raw materials and the yield is still good; 3) methoxy-methyl acetate and a ethyl ester catalyzed by sodium metal under Claisen condensation to be sodium acetate, and urea to be products of direct addition, the prospect of a better method, but not a very good yield.

Green enzyme amine

Green enzyme amine chemical name 2 - amino -3 - mercapto–3 - a carboxylic acid butyrate, is an important Pharmaceutical Intermediates for the synthesis of the treatment of arthritis, chronic hepatitis and AIDS drugs. Green enzyme amine is a chiral compound, with about two spin structures, the traditional synthetic route is received from the penicillin degradation, degradation of the use of some pro-nucleophiles, such as phenylhydrazine, hydrazine hydrate, etc. amine D-Green enzyme extraction; study at home and abroad in recent years, researchers prepared a variety of chemical D, L-Green enzyme amine process, there are 1) first isobutyraldehyde with sulfur, ammonia, reaction of 2 - isopropyl -5,5 - dimethyl -3 - thiazoline, and then after cyanide, hydrolysis, and then into a cyano group carbonyl saponification, and then be open-loop D, L-Green enzyme amine, to be split after acetyl D-Green; 2) to β-bromo - substituting isobutyraldehyde, phenyl ethanol and sodium thiosulfate reaction of β-Phenylethyl Dimethylsulfide isobutyraldehyde, and then react with ammonia, hydrogen cyanide, the formation of cyanide by hydrolysis of benzaldehyde removed by D, L-Green enzyme amine; 3) in recent years the development of some new enzyme intermediates for the synthesis of the Green amines, such as 2 - methyl -4 - isopropyl -5 (4), such as trazodone.

Inter-trifluoromethyl aniline

Inter-trifluoromethyl-aniline are important Pharmaceutical Intermediates, raw materials can be synthesized by the antimalarial mefloquine, anti-inflammatory analgesic fen fluoride acid, niflumic acid, diuretics thiazide benzyl fluoride, hydrogen fluoride thiazine , fluvoxamine antidepressants, analgesics non-diablo-ling, in addition to anti-inflammatory drugs can be synthesized fluoride to eliminate acid butyl ester Monineath fluoride, fluorine Sharon; skin with fungicides difluoro diphenyl urea TFC; anti - prostate drug flutamide and a variety of strong, such as stability and antipsychotics. Reported in the literature between a variety of trifluoromethyl aniline synthetic route, which has been with the development prospects of industrialization based on the route between Trifluoronitrobenzene be as raw materials to restore the inter-trifluoromethyl-aniline, have been successfully developed at home and abroad increases catalytic hydrogen reduction process, the general choice of catalyst Pd / C or high-activity nickel catalyst; Trifluoronitrobenzene between its sources of raw materials there are two routes, one fluorination in order to inter-trichloro-nitrobenzene as raw material through the hydrofluoric acid derived fluoride; Second, nitrification law trifluoromethyl benzene as raw materials to be adopted by mixed acid nitration.

1 - bromo -3 - chloropropane

1 - bromo -3 - chloropropane propylene chloride synthesis by ene reaction with hydrogen bromide. Mass production of the product abroad, can be used in a variety of synthetic drugs, such as the treatment of the sequelae of cerebral thrombosis drug pentoxifylline B, chloride hydrochloride antidepressant drug, desipramine, coronary vasodilator drug hydrochloride, verapamil hydrochloride, etc., also can be used as raw material for synthetic fragrance. With increasing bromine production, and domestic development of these drugs in relatively good prospects, so 1 - bromo -3 - chloropropane and application in the development of broad prospects.

 

 

from: chemz

The human immunodeficiency virus (HIV) attacks the body’s immune system. A healthy immune system is what keeps you from getting sick.
Because HIV damages your immune system, you are more likely to get sick from bacteria and viruses. It is also harder for your body to fight off these infections when you do get them, so you may have trouble getter better. HIV is the condition that causes acquired immunodeficiency syndrome (AIDS).

HIV can only be passed from person to person through body fluids, such blood, semen and vaginal fluid. Children born to infected mothers can also become infected during pregnancy. The most common ways HIV is passed are:
By having unprotected anal, vaginal or oral sex with an infected person.
By sharing needles and syringes for injecting drugs with an infected person.
What happens after a person gets HIV?
After being infected with HIV, your body works hard to attack the virus. With your body fighting, the virus can’t make as many copies of itself. Even though you still have HIV, you’ll begin to look well and feel well again. The usual blood tests will be normal.

However, during this time, the virus is still attacking your lymph nodes. Lymph nodes are the centers of your body’s immune system. The virus may also attack your brain tissue and slowly cause damage there.
Over 10 to 15 years, HIV kills so many CD4 cells that your body can no longer fight off infections. When your CD4 cell count is 200 or less per mL, you have AIDS (a normal count is 600 to 1000). Once you have AIDS (which stands for acquired immunodeficiency syndrome), you can easily catch many serious infections.
Now, I will introduce  4-Nitrophenyl Chloroformate (CAS:7693-46-1) to you.

 

 

 

 

This is used as a pharmaceutical Intermediates of anti-HIV.

 

 

from:timepharm|anti-HIV

Human immunodeficiency virus (HIV ) is a lentivirus (a member of the retrovirus family) that causes acquired immunodeficiency syndrome (AIDS), a condition in humans in which the immune system begins to fail, leading to life-threatening opportunistic infections. Infection with HIV occurs by the transfer of blood, semen, vaginal fluid, pre-ejaculate, or breast milk. Within these bodily fluids, HIV is present as both free virus particles and virus within infected immune cells. The four major routes of transmission are unsafe sex, contaminated needles, breast milk, and transmission from an infected mother to her baby at birth (Vertical transmission). Screening of blood products for HIV has largely eliminated transmission through blood transfusions or infected blood products in the developed world.

HIV infection in humans is considered pandemic by the World Health Organization (WHO). From its discovery in 1981 to 2006, AIDS killed more than 25 million people. HIV infects about 0.6% of the world's population. In 2005 alone, AIDS claimed an estimated 2.4–3.3 million lives, of which more than 570,000 were children. A third of these deaths are occurring in sub-Saharan Africa, retarding economic growth and increasing poverty. According to current estimates, HIV is set to infect 90 million people in Africa, resulting in a minimum estimate of 18 million orphans. Antiretroviral treatment reduces both the mortality and the morbidity of HIV infection, but routine access to antiretroviral medication is not available in all countries.

HIV infects primarily vital cells in the human immune system such as helper T cells (to be specific, CD4+ T cells), macrophages, and dendritic cells. HIV infection leads to low levels of CD4+ T cells through three main mechanisms: First, direct viral killing of infected cells; second, increased rates of apoptosis in infected cells; and third, killing of infected CD4+ T cells by CD8 cytotoxic lymphocytes that recognize infected cells. When CD4+ T cell numbers decline below a critical level, cell-mediated immunity is lost, and the body becomes progressively more susceptible to opportunistic infections.

Most people infected with HIV eventually develop AIDS. These individuals mostly die from opportunistic infections or malignancies associated with the progressive failure of the immune system. HIV progresses to AIDS at a variable rate affected by viral, host, and environmental factors; HIV-specific treatment delays this process. Most will progress to AIDS within 10 years of HIV infection: some will have progressed much sooner, and some will take much longer. Treatment with anti-retrovirals increases the life expectancy of people infected with HIV. Even after HIV has progressed to diagnosable AIDS, the average survival time with antiretroviral therapy was estimated to be more than 5 years as of 2005. Without antiretroviral therapy, someone who has AIDS typically dies within a year.

Bevirimat is an anti-HIV drug derived from a betulinic acid-like compound, first isolated from Syzygium claviflorum, a Chinese herb. It is believed to inhibit HIV by a novel mechanism, so-called maturation inhibition.  It is not currently U.S. Food and Drug Administration (FDA) approved, but is undergoing clinical trials conducted by the pharmaceutical company Panacos. Myriad Genetics announced on January 21, 2009 the acquisition of all rights to Bevirimat for $7M USD.

In December 2007, some results of the Phase IIb trial were released. Thomson Financial News reported that, "some patients respond 'very well' to the Pharmaceutical Intermediates   drug, while another population 'does not respond as well at current dose levels.'" Panacos said it intends to add a group to the study at a higher dosage. The Pharmaceutical Intermediates manufacturers , Panacos, has stated that success with Bevirimat hinges on a patient's particular HIV not having a specific group of genetic mutations in HIV’s Gag protein. When they evaluated the study participants’ virus and found that the participant’s virologic response depended greatly on whether or not the Gag protein of a participant’s virus had polymorphisms—multiple mutations in the protein’s structure. After sampling the virus of 100 patients in the company’s database, they found that about 50 percent did not have Gag polymorphisms, meaning that about 50 percent would likely respond well to the drug. 

According to the only currently available study, "the mean terminal elimination half-life of bevirimat ranged from 56.3 to 69.5 hours, and the mean clearance ranged from 173.9 to 185.8 mL/hour." 
Like protease inhibitors, bevirimat and other maturation inhibitors interfere with protease processing of newly translated HIV polyprotein precursor, called gag. This molecule contains a number of HIV proteins in a single polypeptide which is then cleaved by the enzyme protease to produce functional structural proteins. However, unlike the protease inhibitors, bevirimat binds the gag protein, not protease. Once bound to gag, bevirimat prevents a critical cleavage at a site called the capsid-SP1 junction. The resulting virus particles lack functional capsid protein and have structural defects, rendering them incapable of infecting other cells. For reasons not entirely understood, protease inhibitor-resistant HIV-1 was hypersensitive to bevirimat in vitro. In 2010 a study about bevirimat resistance prediction based on HIV-1 genotype has been published.

 

 

from:wiki

Polyethylenimine (PEI, MW=750 kDa), 4-nitrophenyl chloroformate , high retention dialysis tubing (cut off=12 kDa), Copper grids (200×125 μm2 pitch with 55% open area) for TEM sample preparation, (3-(4,5-dimethyl-thiazole-2-yl)-2,5-diphenyl tetrazolium bromide) (MTT), agarose, HEPES, Tris, EDTA, ethidium bromide (EtBr), bromophenol blue (BPB), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDAC) and xylene cyanol (XC) were procured from Sigma Chemical Co., St. Louis, MO, USA. Polyethylene glycol 6000, BioChemika Ultra (PEG6000 mol. wt. range=5000–7000), Polyethylene glycol 8000, BioChemika Ultra (PEG8000 mol. wt. range=7000–9000) and formvar 15/95E were purchased from Fluka Chemie GmbH.

All other chemicals and reagents were procured locally. Nanoparticles were sonicated using Misonix 3000 sonicator, West Chester PA, USA, with total sonication time of 3 min (6×30 s pulse each followed by a 30 s stop time) at 4 °C (ice-bath) with power set at 3 W using micro tip probe. Characterization was carried out on Fei-Philips Morgagni 268D Transmission Electron Microscope (TEM) from FEI Inc., Hillsboro, Oregon, USA, and particle size analyzer PHOTOCOR FC from Photocor Instruments, College Park, MD, USA.

FTIR spectra were recorded on a single beam Perkin Elmer (Spectrum BX Series), USA, with the following scan parameters: scan range=4400–400 cm−1: number of scan=16: resolution=4.0 cm−1: interval=1.0 cm−1: units=%T. Luciferase activity was measured on Packard Lumicount microplate luminometer, Frankfurt, Germany. GFP expression was observed under Nikon Eclipse TE 2000-U inverted microscope, Kanagawa, Japan, fitted with C–Fl epifluorescence filter block B-2A consisting of excitation filter Ex 450–490 nm, Dichroic mirror DM 505 and barrier filter BA 520. Qiagen kit for plasmid isolation was purchased from Qiagen Inc., CA, USA. Cell culture media, Dulbecco's modified eagle's medium (DMEM), and fetal calf serum (FCS) were from GIBCO-BRL-Life Technologies, Web Scientific Ltd, UK.

 

 

 

 

 

Polyethylene glycol (MW=6 kDa, 6.0 g, ∼1.0 mmol) was dried twice by co-evaporation with dry toluene (100 ml) on a rotary evaporator. Finally, it was dissolved in ethylene dichloride (EDC) (25 ml) and afterwards 4-nitrophenyl chloroformate (604 mg, 3.0 mmol) was added. The solution was stirred and triethylamine (415 μl, 3.0 mmol) was added drop-wise through a syringe over a period of 5 min. The reaction mixture was allowed to stir at room temperature for 6 h. The completion of the reaction was monitored on TLC and the reaction mixture was diluted with EDC (100 ml). Subsequently, it was washed with saturated sodium chloride solution (2×25 ml) and the organic phase was collected and dried over anhydrous sodium sulfate. The solvent was removed under vacuum to obtain polyethylene glycol (6000)-bis (4-Nitrophenyl Chloroformate GC 96% ) (PEG6000-bis–NPC) (5.38 g) in ∼85% yield .
Add commentAdd assertion

Similarly, polyethylene glycol (MW=8 kDa) was reacted with 4-Nitrophenyl Chloroformate Titration 98% to obtain polyethylene glycol (8000)-bis (4-nitrophenylcarbonate) (PEG8000-bis–NPC) (7.2 g) in ∼87% yield.

 

 

from:surguy.net

 

 From: http://www.blogigo.com/timephram

The field of medicine as an important fine chemical industry has become over the past decade the focus of development and competitiveness, with the progress of science and technology, many Chinese medicine has been continuously developed for the benefit of humanity, these Chinese medicine relies on new synthesis of high-quality the production of pharmaceutical intermediates , new drugs are patent-protected, and not compatible with the existence of intermediate problems, so the new pharmaceutical intermediates and application of domestic and foreign markets are very optimistic about the prospects. Many new varieties of pharmaceutical intermediates, can not be fully introduced, this paper began to study in Taiwan in recent years, great concern a new type of pharmaceutical intermediates and pharmaceutical intermediates for a number of important new technology.

For example: 2-Chloro-4, 6-Dimethoxy-1, 3, 5-Triazine  CAS:3140-73-6 

 
Description: 2-Chloro-4, 6-Dimethoxy-1, 3, 5-Triazine
Synonym: CDMT
CAS: 3140-73-6
Assay:  ≥99% (GC)
Appearance: white crystalline powder
Molecular: C5H6ClN3O2
Application: Anti-neoplastic as pharmaceutical intermediates

http://www.timepharm.com/category/pharmaceutical-intermediates-2087-d2ac/1Antibody tests may give false negative (no antibodies were detected despite HIV being present) results during the window period, an interval of three weeks to six months between the time of HIV infection and the production of measurable antibodies to HIV seroconversion. Most people develop detectable antibodies approximately 30 days after infection, although some seroconvert later. The vast majority of people (99%) have detectable antibodies by three months after HIV infection; a six-month window is extremely rare with modern antibody testing. During the window period, an infected person can transmit HIV to others although their HIV infection may not be detectable with an antibody test. Antiretroviral therapy during the window period can delay the formation of antibodies and extend the window period beyond 12 months. This was not the case with patients that underwent treatment with post exposure prophylaxis (PEP). Those patients must take ELISA tests at various intervals after the usual 28 day course of treatment, sometimes extending outside of the conservative window period of 6 months. Antibody tests may also yield false negative results in patients with X-linked agammaglobulinemia; other diagnostic tests should be used in such patients.

Three instances of delayed HIV seroconversion occurring in health-care workers have been reported; in these instances, the health-care workers tested negative for HIV antibodies greater than 6 months postexposure but were seropositive within 12 months after the exposure.DNA sequencing confirmed the source of infection in one instance. Two of the delayed seroconversions were associated with simultaneous exposure to hepatitis C virus (HCV). In one case, co-infection was associated with a rapidly fatal HCV disease course; however, it is not known whether HCV directly influences the risk for or course of HIV infection or is a marker for other exposure-related factors.

Tests selected to screen donor blood and tissue must provide a high degree of confidence that HIV is not present (that is, a high sensitivity). A combination of antibody, antigen and nucleic acid tests are used by blood banks in Western countries. The World Health Organization estimated that, as of 2000, inadequate blood screening had resulted in 1 million new HIV infections worldwide.

In the USA, since 1985, all blood donations are screened with an ELISA test for HIV-1 and HIV-2, as well as a nucleic acid test. These diagnostic tests are combined with careful donor selection. As of 2001[update], the risk of transfusion-acquired HIV in the U.S. was approximately one in 2.5 million for each transfusion.

Now,there is the best medicine,that was discovered,anti-HIV. And Pharmaceutical Intermediates<a href=http://www.timepharm.com/category/pharmaceutical-intermediates-2087-d2ac/1>Pharmaceutical Intermediates<a/> is the best element.

FIGHT FOR HEALTH, THINKING GOES FIRST
Everyday, when we open the television, countless of drug advertisings for “affluenza” begin to flood our eyes. Many people feel disgust to the advertisings and scared the disease, because they know that such a lot people nearing are suffering with this disease but could not do anything about it. It just like a child lost in the forest that does not know which path could lead him out.

In my mind, difficult things are as enemies on the battlefield. The most you want to beat them, the first you have do, is to have a detailed recognition to them, then you could choose a way to “get rid of them”.

First of all, we must to know what is hyperlipemia? The reason to cause it and the result it will cause. Human body is a modern metropolis, dominated by intricate and complicated transport lines – the blood vessel – each moment. Because the body used them to transport oxygen and nutritive materials to different organs, and to transport CO2 and some “trash” out. It is well known that nourishment, such as cholesterol and vitamin D, are necessary and useful for our body and brain, but this does not mean the more we take in, the smarter and healthier we will be. Things always have two sides that opposite to each other, and right will turn to wrong if it is done too much to brake the line. nourishment are these things which were called “wealthy food ”. If they are took in but not completely ingested by your body, the superfluous will stay and accumulate on your inner artery wall to form plaque . LDL (low-density lipoprotein) are believed the worst aliment when it was take in excess. It will adhere on the inner artery wall and accumulate. The artery will be blocked if the acumulated LDL is too much, and bad things will come. For example, If an obstruction occurs in the coronary arteries, it could result in a heart attack. And, if an obstruction occurs in the arteries of the brain, it could lead to stroke.

Two ways could be chose for reducing the LDL’s percentage in the body. First and main way is to take in food with smaller fat or small fat food to reduce fat’s quantity; the other is use something (always drugs) to consume the superfluous fat (include LDL). We all believe believe the most useful method is to form a good diet habit, but an effective drug used in auxiliary can not only relieve the the patient’s pain, but also give the courage to beat hyperlipemia.

Lipid-lowering drugs mainly include statins, fibrates, nicotinic acid and bile acid sequestrants. They have functions on different kind of fat, but the purpose is same – to reduce the fat. For example, fibrates are more active in reducing triglyceride than reducing cholesterol, while HMG-Co A (3-hydroxy-3-methylglutary coenzyme A) are main active on reducing cholesterol with high effects. Recently, a compound medicine of Ezetimibe was released to used as reducing cholesterol drug. (It is honored that one of our product — 2-Chloro-4,6-dimethoxy-1,3,5-triazine — could be used as one of its intermediates. A research from Britain indicates that this drug has higher effects on reducing cholesterol than others.

Progress in culture and technology let us pay closer attention to health. We want to fight for health along with all Pharmaceutical corporates to make life more beautiful and colorful.

Reference from: Time-Chem http://www.timepharm.com/news/item_668.html

Reprinted from: Pharmaceutical Intermediates

Chemical companies will increase their capital spending 8.6% to nearly $8.8 billion, according to an early February survey of 17 companies by Chemical & Engineering News. For 2007, C&EN reports that the actual capital spending of the 18 companies surveyed increased by 13.2% to $8.1 billion. These companies include Dawnrays Pharmaceutical (Holdings) Ltd., Suzhou Time-chem Technologies, Nanjing Source Chemical Co., Ltd., and so on. Survey results from 14 companies indicate R&D spending will grow 6.0% to $2.8 billion in 2008. The budgets for 2008 indicate that 71.5% of funds will go towards capital projects and 28.5% towards R&D. The American Chemistry Council (ACC) anticipates that 2008 capital spending for basic and specialty chemical companies will increase by 6.3% and R&D spending will increase by 4.4%. The ACC also reports that over the long term, its members will reduce the US share of their total capital spending budgets from 62% in 2006 to 48% in 2011. The Synthetic Organic Chemical Manufacturers also released a survey of its members, with 75% reporting that they would increase their R&D investment between 2% and 10%, with the mean investment being 8.6% of sales. Of those surveyed, 38% claimed that they are very likely or somewhat likely to increase their capital spending for 2008, with a mean investment of 10.8% of sales.