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A new nonsurgical approach to treating chronic pain and stiffness associated with knee osteoarthritis has demonstrated significant, lasting improvement in knee pain, function, and stiffness. This safe, two-solution treatment delivered in a series of injections into and around the knee joint is called prolotherapy.

David Rabago, MD, and a team of researchers from the University of Wisconsin School of Medicine and Public Health, and Meriter Health Services, Madison, WI, report substantial improvement among participants in the one-year study who received at least three of the two-solution injections. Symptom improvement ranged from 19.5-42.9% compared to baseline status.

As described in the article “Dextrose and Morrhuate Sodium Injections (Prolotherapy) for Knee Osteoarthritis: A Prospective Open-Label Trial“, reported improvement in knee pain, function, and stiffness scores exceeded the minimum for a “clinically important difference” in 50-75% of patients.

Here is the full text of this article: http://online.liebertpub.com/doi/full/10.1089/acm.2013.0225

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Apigenin: this chemical breaks the immortality of cancer cells

April 9, 2014 10:24 am / 1 Comment on Apigenin: this chemical breaks the immortality of cancer cells

Apigenin, which abounds in particular parsley, have protective effects against cancer. Indeed, a U.S. study showed that apigenin alters the process of gene regulation in cancer cells, which has the effect of making them sensitive to the new process of cell death. Credits: H. Zell

Apigenin, a very natural chemical compound present in the Mediterranean diet, breaks immortality of cancer cells. A result obtained by researchers at the Ohio State University (USA).

http://www.journaldelascience.fr/sante/articles/apigenine-compose-chimique-naturel-cellules-cancereuses-mortelles-3090

apigenin

Apigenin is found in many fruits and vegetables, but parsley, celery and chamomile tea are the most common sources

DRUG PROCESS CHEMISTRY

April 9, 2014 8:06 am / 2 Comments on DRUG PROCESS CHEMISTRY

Process chemistry is the arm of pharmaceutical chemistry concerned with the development and optimization of a synthetic scheme and pilot plant procedure to manufacture compounds for the drug development phase. Process chemistry is distinguished from medicinal chemistry, which is the arm of pharmaceutical chemistry tasked with designing and synthesizing molecules on small scale in the early drug discovery phase.

Medicinal chemists are largely concerned with synthesizing a large number of compounds as quickly as possible from easily tunable chemical building blocks (usually for SAR studies). In general, the repertoire of reactions utilized in discovery chemistry is somewhat narrow (for example, the Buchwald-Hartwig amination, Suzuki coupling and reductive amination are commonplace reactions).^[1] In contrast, process chemists are tasked with identifying a chemical process that is safe, cost and labor efficient, “green,” and reproducible, among other considerations.

Oftentimes, in searching for the shortest, most efficient synthetic route, process chemists must devise creative synthetic solutions that eliminate costly functional group manipulations and oxidation/reduction steps.

This article will focus exclusively on the chemical and manufacturing processes associated with the production of small molecule drugs. Biological medical products (more commonly called “biologics”) represent a growing proportion of approved therapies, but the manufacturing processes of these products are beyond the scope of this article.

Additionally, the many complex factors associated with chemical plant engineering (for example, heat transfer and reactor design) and drug formulation will be treated cursorily.

Process Chemistry Considerations

Cost efficiency is of paramount importance in process chemistry and, consequently, is a focus in the consideration of pilot plant synthetic routes. The drug substance that is manufactured, prior to formulation, is commonly referred to as the active pharmaceutical ingradient (API) and will be referred to as such herein.

API production cost can be broken into two components: the “material cost” and the “conversion cost.”^[2] The ecological and environmental impact of a synthetic process should also be evaluated by an appropriate metric (e.g. the EcoScale).

An ideal process chemical route will score well in each of these metrics, but inevitably tradeoffs are to be expected. Most large pharmaceutical process chemistry and manufacturing divisions have devised weighted quantitative schemes to measure the overall attractiveness of a given synthetic route over another. As cost is a major driver, material cost and volume-time output are typically weighted heavily.

The chemical and processing industries (CPI) provide the building blocks for many products. By using large amounts of heat and energy to physically or chemically transform materials, these industries help meet the world’s most fundamental needs for food, shelter and health, as well as products that are vital to such advanced technologies as computing, telecommunications and biotechnology.

These industries face major challenges to meet the needs of the present without compromising the needs of the future generations in the face of increasing industrial competitiveness. This translates into the need to make processes much more energy efficient, safer and more flexible, and to reduce emissions to meet the many competitive challenges within a global economy.

The chemical and processing industries refer to processes where materials undergo chemical conversion during their production into finished products, as well as – or instead of – the physical conversions common to industry in general.

In the chemical process industry the products differ chemically from the raw materials as a result of undergoing one or more chemical reactions during the manufacturing process.

The chemical process industries broadly include the traditional chemical industries, both organic and inorganic; the petroleum industry; the petrochemical industry, which produces the majority of plastics, synthetic fibers, and synthetic rubber from petroleum and natural-gas raw materials; and a series of allied industries in which chemical processing plays a substantial part.

While the chemical process industries are primarily the realm of the chemical engineer and the chemist, they also involve a wide range of other scientific, engineering, and economic specialists.

Material Cost

The material cost of a chemical process is the sum of the costs of all raw materials, intermediates, reagents, solvents and catalysts procured from external vendors. Material costs may influence the selection of one synthetic route over another or the decision to outsource production of an intermediate.

Conversion Cost

The conversion cost of a chemical process is a factor of that procedure’s overall efficiency, both in materials and time, and its reproducibility. The efficiency of a chemical process can be quantified by its atom economy, yield, volume-time output, and environmental factor (E-factor), and its reproducibility can be evaluated by the Quality Service Level (QSL) and Process Excellence Index (PEI) metrics.

An illustrative example of atom economy using the Claisen rearrangement and Wittig reaction.

Atom Economy

The atom economy of a reaction is defined as the number of atoms from the starting materials that are incorporated into the final product. Atom economy can be viewed as an indicator of the “efficiency” of a given synthetic route.^[3]

$AE = \frac{\text{MW(product)}}{\sum \text{MW(raw materials)}}*100%$

For example, the Claisen rearrangement and the Diels-Alder cycloaddition are examples of reaction that are 100 percent atom economical. On the other hand, a prototypical Wittig reaction has especially poor atom economy (merely 20 percent in the example shown).

Process synthetic routes should be designed such that atom economy is maximized for the entire synthetic scheme. Consequently, “costly” reagents such as protecting groups and high molecular weight leaving groups should be avoided where possible. An atom economy value in the range of 70 to 90 percent for an API synthesis is ideal, but it may be impractical or impossible to access certain complex targets within this range. Nevertheless, atom economy is a good metric to compare two routes to the same molecule.

Yield

Yield is defined as the amount of product obtained in a chemical reaction. According to Vogel’s Textbook of Practical Organic Chemistry, yields around 100% are called quantitative, yields above 90% are excellent, yields above 80% are very good, yields above 70% are good, yields above 50% are fair, and yields below 40% are poor. The yield that has practical significance in a process chemistry setting is the isolated yield, referring to the yield of the isolated product after all extraction and purification steps. In a final API synthesis, isolated yields of 80 percent or above for each synthetic step are expected.

An illustrative example of convergent synthesis.

There are several strategies that are employed in the design of a process route to ensure adequate overall yield of the pharmaceutical product. The first is the concept of convergent synthesis. Assuming a very good to excellent yield in each synthetic step, the overall yield of a multistep reaction can be maximized by combining several key intermediates at a late stage that are prepared independently from each other.

Another strategy to maximize isolated yield (as well as time efficiency) is the concept of telescoping synthesis (also called one-pot synthesis). This approach describes the process of eliminating workup and purification steps from a reaction sequence, typically by simply adding reagents sequentially to a reactor. In this way, unnecessary losses from these steps can be avoided.

Finally, to minimize overall cost, synthetic steps involving expensive reagents, solvents or catalysts should be designed into the process route as late stage as possible, to minimize the amount of reagent used.

In a pilot plant or manufacturing plant setting, yield can have a profound effect on the material cost of an API synthesis, so the careful planning of a robust route and the fine-tuning of reaction conditions are crucially important. After a synthetic route has been selected, process chemists will subject each step to exhaustive optimization in order to maximize overall yield. Low yields are typically indicative of unwanted side product formation, which can raise red flags in the regulatory process as well as pose challenges for reactor cleaning operations.

Volume-Time Output

The volume-time output (VTO) of a chemical process represents the cost of occupancy of a chemical reactor for a particular process or API synthesis. For example, a high VTO indicates that a particular synthetic step is costly in terms of “reactor hours” used for a given output. Mathematically, the VTO for a particular process is calculated by the total volume of all reactors (m³) that are occupied times the hours per batch divided by the output for that batch of API or intermediate (measured in kg).

$VTO=\frac{\text{nominal volume of all reactors} [m^3]*\text{time per batch} [h]}{\text{output per step} [kg]}$

The process chemistry group at Boehringer-Ingelheim, for example, targets a VTO of less than 1 for any given synthetic step or chemical process.

Additionally, the raw conversion cost of an API synthesis (in dollars per batch) can be calculated from the VTO, given the operating cost and usable capacity of a particular reactor. Oftentimes, for large-volume APIs, it is economical to build a dedicated production plant rather than to use space in general pilot plants or manufacturing plants.

Environmental Factor (E-factor) and Process Mass Intensity (PMI)

Both of these measures, which capture the environmental impact of a synthetic reaction, intend to capture the significant and rising cost of waste disposal in the manufacturing process. The E-factor for an entire API process is computed by the ratio of the total mass of waste generated in the synthetic scheme to the mass of product isolated.
$E=\frac{\sum \text{mass of waste}}{\text{mass of isolated product}}=\frac{\sum \text{mass of materials}-\text{mass of isolated product}}{\text{mass of isolated product}}$
A similar measure, the process mass intensity (PMI) calculates the ratio of the total mass of materials to the mass of the isolated product.
$PMI=\frac{\sum \text{mass of materials}}{\text{mass of isolated product}}$
For both metrics, all materials used in all synthetic steps, including reaction and workup solvents, reagents and catalysts, are counted, even if solvents or catalysts are recycled in practice. Inconsistencies in E-factor or PMI computations may arise when choosing to consider the waste associated with the synthesis of outsourced intermediates or common reagents. Additionally, the environmental impact of the generated waste is ignored in this calculation; therefore, the environmental quotient (EQ) metric was devised, which multiplies the E-factor by an “unfriendliness quotient” associated with various waste streams. A reasonable target for the E-factor or PMI of a single synthetic step is any value between 10 and 40.

Quality Service Level (QSL)

The final two “conversion cost” considerations involve the reproducibility of a given reaction or API synthesis route. The quality service level (QSL) is a measure of the reproducibility of the quality of the isolated intermediate or final API. While the details of computing this value are slightly nuanced and unimportant for the purposes of this article, in essence, the calculation involves the ratio of satisfactory quality batches to the total number of batches. A reasonable QSL target is 98 to 100 percent.

Process Excellence Index (PEI)

Like the QSL, the process excellence index (PEI) is a measure of process reproducibility. Here, however, the robustness of the procedure is evaluated in terms of yield and cycle time of various operations. The PEI yield is defined as follows:

$\text{PEI yield}=\frac{\text{average yield}*100%}{\text{aspiration level yield}}=\frac{\text{average yield}*100%}{\frac{\text{median yield}+\text{best yield}}{2}}$
In practice, if a process is high-yielding and has a narrow distribution of yield outcomes, then the PEI should be very high. Processes that are not easily reproducible may have a higher aspiration level yield and a lower average yield, lowering the PEI yield.

Similarly, a PEI cycle time may be defined as follows:

$\text{PEI cycle time}=\frac{\text{aspiration level cycle time}*100%}{\text{average cycle time}}=\frac{\frac{\text{median cycle time}+\text{best cycle time}}{2}}{\text{average cycle time}}$
For this expression, the terms are inverted to reflect the desirability of shorter cycle times (as opposed to higher yields). The reproducibility of cycle times for critical processes such as reaction, centrifugation or drying may be critical if these operations are rate-limiting in the manufacturing plant setting. For example, if an isolation step is particularly difficult or slow, it could become the bottleneck for an API synthesis, in which case the reproducibility and optimization of that operation become critical.

For an API manufacturing process, all PEI metrics (yield and cycle times) should be targeted at 98 to 100 percent.

EcoScale

In 2006, Van Aken, et al.^[4] developed a quantitative framework to evaluate the safety and ecological impact of a chemical process, as well as minor weighting of practical and economical considerations. Others have modified this EcoScale by adding, subtracting and adjusting the weighting of various metrics. Among other factors, the EcoScale takes into account the toxicity, flammability and explosive stability of reagents used, any nonstandard or potentially hazardous reaction conditions (for example, elevated pressure or inert atmosphere), and reaction temperature. Some EcoScale criteria are redundant with previously considered criteria (e.g. E-factor).

Synthetic Case Studies

Boehringer Ingelheim HCV Protease Inhibitor (BI 201302)

Macrocyclization is a recurrent challenge for process chemists, and large pharmaceutical companies have necessarily developed creative strategies to overcome these inherent limitations. An interesting case study in this area involves the development of novel NS3 protease inhibitors to treat Hepatitis C patients by scientists at Boehringer-Ingelheim.^[5] The process chemistry team at BI was tasked with developing a cheaper and more efficient route to the active NS3 inhibitor BI 201302, a close analog of BILN 2061. Two significant shortcomings were immediately identified with the initial scale-up route to BILN 2061, depicted in the scheme below.^[6] The macrocyclization step posed four challenges inherent to the cross-metathesis reaction.

High dilution is typically necessary to prevent unwanted dimerization and oligomerization of the diene starting material. In a pilot plant setting, however, a high dilution factor translates into lower throughput, higher solvent costs and higher waste costs.
High catalyst loading was found to be necessary to drive the RCM reaction to completion. Because of high licencing costs of the ruthenium catalyst that was used (1st generation Hoveyda catalyst), a high catalyst loading was financially prohibitive. Recycling of the catalyst was explored, but proved impractical.
Long reaction times were necessary for reaction completion, due to slow kinetics of the reaction using the selected catalyst. It was hypothesized that this limitation could be overcome using a more active catalyst. However, while the second-generation Hoveyda and Grubbs catalysts were kinetically more active than the first-generation catalyst, reactions using these catalysts formed large amounts of dimeric and oligomeric products.
An epimerization risk under the cross-methathesis reaction conditions. The process chemistry group at Boehringer-Ingelheim performed extensive mecahnistic studies showing that epimerization most likely occurs through a ruthenacyclopentene intermediate.^[7] Furthermore, the Hoveyda catalyst employed in this scheme minimizes epimerization risk compared with the alalogous Grubbs catalyst.

Additionally, the final double S_N2 sequence to install the quinoline heterocycle was identified as a secondary inefficiency in the synthetic route.

Analysis of the cross-methathesis reaction revealed that the conformation of the acyclic precursor had a profound impact on the formation of dimers and oligomers in the reaction mixture. By installing a Boc protecting group at the C-4 amide nitrogen, the Boehringer-Ingelheim chemists were able to shift the site of initiation from the vinylcyclopropane moiety to the nonenoic acid moiety, improving the rate of the intramolecular reaction and decreasing the risk of epimerization. Additionally, the catalyst employed was switched from the expensive 1^st generation Hoveyda catalyst to the more reactiveless expensive Grela catalyst.^[8] These modifications allowed the process chemists to run the reaction at a standard reaction dilution of 0.1-0.2 M, given that the rates of competing dimerization and oligomerization reactions was so dramatically reduced.

Additionally, the process chemistry team envisioned a S_NAr strategy to install the quinoline heterocycle, instead of the S_N2 strategy that they had employed for the synthesis of BILN 2061. This modification prevented the need for inefficient double inversion by proceeding through retention of stereochemistry at the C-4 position of the hydroxyproline moiety.^[9]

It is interesting to examine this case study from a VTO perspective. For the unoptimized cross-metathesis reaction using the Grela catalyst at 0.01 M diene, the reaction yield was determined to be 82 percent after a reaction and workup time of 48 hours. A 6-cubic meter reactor filled to 80% capacity afforded 35 kg of desired product. For the unoptimized reaction:

This VTO value was considered prohibitively high and a steep investment in a dedicated plant would have been necessary even before launching Phase III trials with this API, given its large projected annual demand. But after reaction development and optimization, the process team was able to improve the reaction yield to 93 percent after just 1 hour (plus 12 hours for workup and reactor cleaning time) at a diene concentration of 0.2 M. With these modifications, a 6-cubic meter reactor filled to 80% capacity afforded 799 kg of desired product. For this optimized reaction:

Thus, after optimization, this synthetic step became less costly in terms of equipment and time and more practical to perform in a standard manufacturing facility, eliminating the need for a costly investment in a new dedicated plant.

Simvastatin, originally developed by Merck, is the most frequently prescribed statin today, with more nearly 100 million prescriptions filled in 2010, according to IMS Health. The traditional synthesis of the drug entailed a multi-step chemical process starting from Lovastatin. The chemical process was using large amounts of hazardous reagents as well as large quantities of solvents.

Professor Yi Tang, at UCLA conceived an initial synthesis that used an engineered enzyme. Codexis Inc. licensed the intellectual property from UCLA, optimized the initial enzyme and developed the new process for commercial use as shown in Figure 1. Following the quantitative hydrolysis of lovastatin to monacolin J acid, Codexis developed a novel, non-natural acyl donor enzyme to regioselectively acylate the C8 position and effect cyclization to simvastatin. This mild bioenzymatic process reduces the 4 steps chemical synthesis to only two steps. The Codexis process is significantly more efficient, cost effective and environmentally friendly.

This is the reaction scheme for producing the drug Simvastatin. The process was an award-winner at last month’s Green Chemistry Challenge Awards held by the Environmental Protection Agency

“We started working on Simvastatin in 2008 and completed the planning process in 2010,” Huisman said. “Then, we started the commercialization process, which takes time because you need regulatory approval of the new process we were working on. We licensed some technology from Yi Tang and UCLA and were then able to continue.”

Codexis took the three-step process used to make Simvastatin and cut out two of the steps, Huisman said.

“From the starting material, it (Simvastatin) has three reactive groups, or hydroxy groups, and what we need to do is convert two of the three groups,” Huisman explained. “We took out a protective step and a de-protective step. We took out two of the steps, and it was intense chemical processing. We then were able to accomplish everything in one step. We also circumvented the use of several nasty chemicals, as well.”

By cutting out two steps, “the overall yield goes up tremendously, about 35 percent,” Huisman added. “And we’re generating 25 times less waste than we did in the old process.”

Huisman said the new process doesn’t change the drug’s effects at all, and that scientists have been trying to do this type of work on commercial drugs for decades.

“In order for this to be a commercial process, the enzyme needs to be improved,” he said. “We needed to speed up the enzyme 1,000-fold to make this process workable; it took a team of scientists about nine months to optimize the enzymes and speed it up.”

Codexis 2 step enzymatic process versus the 4 step chemical synthesis

AZIDES

A popular procedure for making 5-substituted tetrazoles is the reaction of sodium azide with a nitrile, often in the presence of an ammonium salt. The example shown below is from Organic Syntheses (Novartis Process R&D and Ley’s group at Cambridge), providing the useful enantiocatalyst shown on an 80 mmol scale. The excess sodium azide was destroyed with sodium nitrite and sulfuric acid, which converts hydrazoic acid into nitrogen and nitrous oxide gases.

While the above procedure may be popular, any time you use sodium azide you should be thinking, “hydrazoic acid can be generated, it’s explosive and toxic, and I need to take the appropriate safety precautions.” That’s precisely what happened during some recent process R&D work at Merck Frosst on the steroyl-CoA desaturase inhibitor MK-8245. The discovery chemistry route used NaN₃/pyridinium chloride as shown below, but the process group felt that the potential for significant amounts of hydrazoic acid generation was too high.

Armed with the ability to detect hydrazoic acid in the headspace above the reaction mixture using online IR, the Merck Frosst researchers surveyed alternatives. Sharpless’s zinc bromide procedure, proposed to minimize hydrazoic acid formation by control of the pH, led to a reading of 2000 ppm of HN₃ in the headspace, which is below the detonation threshold of 15,000 ppm but was still felt to be undesirable. In their own survey of conditions, the Merck Frosst scientists found something quite new and significant: Reaction with sodium azide in the presence of a catalytic amount of zinc oxide in aqueous THF (pH 8) proceeded efficiently, and most notably, with only 2 ppm of HN₃ in the headspace! They were able to make 7 kg of the tetrazole in one run in nearly quantitative yield. Nice!

I’d be remiss if I didn’t mention Bu₃SnN₃ and Me₃SiN₃/Cu(I) as sodium azide surrogates, sometimes used on large scale. Shown below is an application to valsartan (see here and here) with recycling of the tin by-products. The intermediate stannyl tetrazole and leftover Bu₃SnN₃ were converted with HCl to Bu₃SnCl, which was then converted to the fluoride, which was removed by filtration and recycled to Bu₃SnCl.

Additional Topics

Transition-Metal Catalysis and Organocatalysis

Biocatalysis and Enzymatic Engineering

Recently, large pharmaceutical process chemists have relied heavily on the development of enzymatic reactions to produce important chiral building blocks for API synthesis. Many varied classes of naturally occurring enzymes have been co-opted and engineered for process pharmaceutical chemistry applications. The widest range of applications come from ketoreductases and transaminases, but there are isolated examples from hydrolases, aldolases, oxidative enzymes, esterases and dehalogenases, among others.^[10]

One of the most prominent uses of biocatalysis in process chemistry today is in the synthesis of Januvia®, a DPP-4 inhibitor developed by Merck for the management of type II diabetes. The traditional process synthetic route involved a late-stage enamine formation followed by rhodium-catalyzed asymmetric hydrogenation to afford the API sitagliptin. This process suffered from a number of limitations, including the need to run the reaction under a high-pressure hydrogen environment, the high cost of a transition-metal catalyst, the difficult process of carbon treatment to remove trace amounts of catalyst and insufficient stereoselectivity, requiring a subsequent recrystallization step before final salt formation.^[11]^[12]

Merck’s process chemistry department contracted Codexis, a medium-sized biocatalysis firm, to develop a large-scale biocatalytic reductive amination for the final step of its sitagliptin synthesis. Codexis engineered a transaminase enzyme from the bacteria Arthrobacter through 11 rounds of directed evolution. The engineered transaminase contained 27 individual point mutations and displayed activity four orders of magnitude greater than the parent enzyme. Additionally, the enzyme was engineered to handle high substrate concentrations (100 g/L) and to tolerate the organic solvents, reagents and byproducts of the transamination reaction. This biocatalytic route successfully avoided the limitations of the chemocatalyzed hydrogenation route: the requirements to run the reaction under high pressure, to remove excess catalyst by carbon treatment and to recrystallize the product due to insufficient enantioselectivity were obviated by the use of a biocatalyst. Merck and Codexis were awarded the Presidential Green Chemistry Challenge Award in 2010 for the development of this biocatalytic route toward Januvia®.^[13]

ATORVASTATIN

Biocatalytic process development firm Codexis was recognized with the award in the greener reaction conditions category for developing a “green-by-design” enzymatic process to replace a chemical process for making ethyl (R)-4-cyano-3-hydroxybutyrate. This chemical, also known as hydroxynitrile, is the key chiral building block used to make atorvastatin, the active ingredient in Pfizer‘s cholesterol-lowering drug Lipitor.

The new process is helping to lower atorvastatin’s long-term production costs, according to John H. Grate, senior vice president of R&D and chief technology officer at Codexis. The savings could be financially significant for Pfizer and future generics manufacturers given that Lipitor is the world’s top pharmaceutical, with annual sales of about $13 billion.

Hydroxynitrile is used in the early stages of atorvastatin synthesis to build the chiral dihydroxy acid side chain that’s essential to the drug’s activity, Grate told C&EN. Demand for the intermediate is about 200 metric tons per year, and it’s currently being made by several fine chemicals producers. The competition to supply the intermediate to Pfizer has spurred several firms to chase after a better way to prepare hydroxynitrile (Angew. Chem. Int. Ed. 2005, 44, 362).

Chemical engineering professor Galen J. Suppes of the University of Missouri, Columbia, was honored with the academic award for his group’s work to create a low-cost catalytic process to convert the glycerol by-product from biodiesel production into propylene glycol–turning 1,2,3-propanetriol into 1,2-propanediol. At first glance, this achievement may not sound that exciting. But the repercussions of Suppes’s accomplishment are expected to have a major impact on the future use of biodiesel fuel, the world glycerol market, and the environmental health and safety of antifreeze and deicing chemicals.

Photo by Rob Hill/MU Publications

GREEN SOLUTION Suppes and his group uncovered ideal reaction conditions for the catalytic conversion of by-product glycerol to useful propylene glycol.

Biodiesel is a mixture of fatty acid methyl esters made by esterifying soybean oil or other vegetable oil or animal fat. The triglycerides in the oil consist of three long fatty acid chains connected to a propyl headgroup. Sodium hydroxide is used to cleave the chains, which in turn are reacted with methanol to form methyl esters, leaving the residual glycerol headgroup as a by-product. About 1 kg of crude glycerol is formed for every 9 kg of biodiesel produced.

Millions of gallons of glycerol are flooding the world market as biodiesel production is ramping up in the U.S. and Europe, Suppes explained. The fallout from this glycerol glut is that chemical companies have shuttered some glycerol production plants and are considering glycerol as a starting material to make a host of feedstock chemicals (C&EN, Feb. 6, page 7).

Suppes entered the picture about four years ago when he realized that an inexpensive method to convert glycerol to propylene glycol could be valuable, he said. Utilizing the glycerol not only would help offset the cost of biodiesel production, but the inexpensive propylene glycol could be used as a low-toxicity replacement for ethylene glycol in automotive antifreeze.

Suppes’s system involves low-pressure hydrogenolysis of glycerol using a copper chromite catalyst, CuO•Cr2O3 (Appl. Catal. A 2005, 281, 225). In the two-step process, glycerol is first dehydrated to form acetol (1-hydroxy-2-propanone), which is then hydrogenated to form propylene glycol.

GREEN LEFTOVERS Glycerol by-product from biodiesel production can be used as a feedstock in Suppes’ process to produce acetol or propylene glycol from renewable resources.

Copper chromite hydrogenolysis catalysts aren’t new, but the success of the Missouri process is in achieving high selectivity for propylene glycol by controlling the temperature and hydrogen pressure of the reaction, Suppes noted. In the past, researchers tended to use reaction temperatures that were too high, leading to a higher percentage of by-products. Thus, they “missed the window of opportunity to achieve high selectivity,” Suppes said. Tinkering with temperature, pressure, and several different catalysts, Suppes and his colleagues optimized the system to operate at about 220 °C and less than 10 bar versus about 260 °C and more than 150 bar for other systems.

Another key part of the synthesis is the ability to isolate the acetol intermediate, Suppes added. Acetol is a synthetic starting material used to make polyols. But when made from petroleum, it costs about $5.00 per lb, discouraging its widespread use. Suppes envisions that producing acetol from biomass-based glycerol using his process could lower the cost to 50 cents per lb, “opening up even more potential applications and markets for products made from glycerol.”

Suppes’s propylene glycol process has been patented and is being licensed through the Missouri Soybean Merchandising Council, which provided partial funding for the research. The first commercial facility, with an annual capacity of 11.5 million gal, is being built in an undisclosed location in the U.S. by Senergy Chemical. It’s expected to be in operation by the end of this year.

E7398, INN eribulin mesylate

The most awe-inspiring example of a positive tangible outcome from the combination of basic research into the synthesis of a system, and a correctly weighted assessment of ‘scalability’, is Halaven® (2, E7398, INN eribulin mesylate). Most chemists in industry and academia alike would have considered using total synthesis to support clinical development and commercialization of this compound a ‘fool’s errand,’ but the Kishi group and Eisai Inc. did not. The fact is that this compound solves a major clinical problem, so taking on the issues (length of synthesis, stability limitations, stereochemical problems, etc.) had a big payoff (reducing the relative weighting or importance of these factors in assessing the viability of a commercial chemical synthesis). As depicted below, a highly convergent approach, combined with powerful methodology for stitching together key fragments 5 and 6 (Nozaki–Hiyama–Kishi (NHK) coupling) and a strategy of targeting crystalline intermediates were all key elements that culminated in this landmark accomplishment

The commercial synthesis of Halaven® (2), a landmark achievement in process chemistry

Artemisinin (Cook, 2012).

(+)-Artemisinin (41) is currently the most effective drug against Plasmodium falciparum malaria as part of an artemisinin-based combination therapy (ACT). Although it can be isolated on an industrial scale from Artemisia annua, the market price of artemisinin (41) has fluctuated widely and traditional extraction does not provide enough material to meet the worldwide demand. Interestingly, recent efforts towards a cheaper and more efficient production of artemisinin (41) have mainly taken place in the areas of synthetic biology, semisynthesis and plant engineering, while there has been a lack of practical approaches using a straightforward total synthesis. Despite the fact that all the total syntheses of artemisinin, until 2010, were impressive from a feasibility point of view, none of them provided a solution for the low-cost synthesis of 41. This changed when Cook’s group recently published a scalable synthesis of artemisinin (41), which provides a blueprint for the cost-effective production of 41 and its derivatives below Key to their successful strategy was the use of reaction cascades that rapidly built complexity, starting from the cheap feedstock chemical, cyclohexenone (42). The latter was first subjected to a one-pot conjugate addition/alkylation sequence, to give ketone 43. A three-step sequence consisting of formylation, cycloaddition and a Wacker-type oxidation, yielded 9.4 g of methyl ketone 44. The challenging formation of the unusual peroxide bridge was initially met with failure, but was eventually realized by a reaction with singlet oxygen to give 41 amongst other oxidized intermediates. The entire synthetic sequence was conducted on a gram scale, required only three chromatographic purifications and was carried out in only five flasks. Considering the low cost of the commodity chemicals used and the conciseness of Cook’s synthesis, it is certainly worth being further investigated.


	Cook’s scalable route to (+)-artemisinin (41).

Continuous/Flow Manufacturing

In recent years, much progress has been made in the development and optimization of flow reactors for small-scale chemical synthesis (the Jamison Group at MIT and Ley Group at Cambridge University, among others, have pioneered efforts in this field). The pharmaceutical industry, however, has been slow to adopt this technology for large-scale synthetic operations. For certain reactions, however, continuous processing may possess distinct advantages over batch processing in terms of safety, quality and throughput.

A case study of particular interest involves the development of a fully continuous process by the process chemistry group at Eli Lilly and Company for an asymmetric hydrogenation to access a key intermediate in the synthesis of LY500307,^[14] a potent ERβ agonist that is entering clinical trials for the treatment of patients with schizophrenia, in addition to a regimen of standard antipsychotic medications. In this key synthetic step, a chiral rhodium-catalyst is used for the enantioselective reduction of a tetrasubstituted olefin. After extensive optimization, it was found that in order to reduce the catalyst loading to a commercially practical level, the reaction required hydrogen pressure up to 70 atm. The pressure limit of a standard chemical reactor is about 10 atm, although high-pressure batch reactors may be acquired at significant capital cost for reactions up to 100 atm. Especially for an API in the early stages of chemical development, such an investment clearly bears a large risk.

An additional concern was that the hydrogenation product has an unfavorable eutectic point, so it was impossible to isolate the crude intermediate in more than 94 percent ee by batch process. Because of this limitation, the process chemistry route toward LY500307 necessarily involved a kinetically controlled crystallization step after the hydrogenation to upgrade the enantiopurity of this penultimate intermediate to >99 percent ee.

The process chemistry team at Eli Lilly successfully developed a fully continuous process to this penultimate intermediate, including reaction, workup and kinetically controlled crystallization modules (the engineering considerations implicit in these efforts are beyond the scope of this article). An advantage of flow reactors is that high-pressure tubing can be utilized for hydrogenation and other hyperbaric reactions. Because the head space of a batch reactor is eliminated, however, many of the safety concerns associated with running high-pressure reactions are obviated by the use of a continuous process reactor. Additionally, a two-stage mixed suspension-mixed product removal (MSMPR) module was designed for the scalable, continuous, kinetically controlled crystallization of the product, so it was possible to isolate in >99 percent ee, eliminating the need for an additional batch crystallization step.

This continuous process afforded 144 kg of the key intermediate in 86 percent yield, comparable with a 90 percent isolated yield using the batch process. This 73-liter pilot-scale flow reactor (occupying less than 0.5 m³ space) achieved the same weekly throughput as theoretical batch processing in a 400-liter reactor. Therefore, the continuous flow process demonstrates advantages in safety, efficiency (eliminates the need for batch crystallization) and throughput, compared with a theoretical batch process.

US scientists have found a way to stop solid byproducts clogging channels in continuous flow reactors, a problem that has hampered their progress for use in manufacturing pharmaceuticals.

Klavs Jensen, Stephen Buchwald and their team at the Massachusetts Institute of Technology believe that flow methods will become increasingly important in the future of pharmaceuticals and chemical manufacturing. ‘One of the biggest hurdles is handling solids,’ says group member Timothy Noël. ‘Precipitates can form during the reactions, which usually lead to irreversible clogging of microchannels in the reactors.’ Previous methods suggested to overcome this problem include introducing another solvent to dissolve the solids, but this can reduce the overall efficiency of the reactions. Now, the team have used an ultrasound bath to break up the byproducts to prevent clogging.

Traditionally, pharmaceutical manufacture is done in a batch-based system, but the process suffers from interruptions and the need to transport material between batch reactors. Performing these reactions in a continuous flow system would speed up the process and reduce chemical waste.

Unclogging the problems of flow chemistry

Reagents were introduced into a tube, which was then placed in an ultrasonic bath heated to 60 degrees Celsius. When the reagents exited the reactor, the reaction was mixed with a quench of water and ethyl acetate in a larger tube, allowing plenty of time for salt byproducts to dissolve

The team tested the method on palladium-catalysed C-N cross-coupling reactions, making amines that are common in biologically active molecules. The reactions couple aryl halides to nitrogen nucleophiles and form byproducts – inorganic salts – that are insoluble in the solvents used.

As a result, says Noël, they were able to obtain diarylamine products with reaction times ranging from 20 seconds to 10 minutes. At very short residence times (time in the reactor under reaction conditions) they observed a significantly higher rate for the reaction in flow compared to the equivalent batch experiments. With high conversions in short reaction times, they were able to reduce the catalyst loading in flow to just 0.1 mol per cent. ‘Extremely low catalyst loadings such as these are of particular interest to the pharmaceutical industry,’ says Noël.

Noël believes that in the future microfluidics will be used to construct increasingly complex molecules. Different devices will automate and integrate many synthetic steps that are currently performed using the more traditional and time-consuming batch-based practices.

Oliver Kappe, from the Christian Doppler Laboratory for Microwave Chemistry, Institute of Chemistry, Karl-Franzens-University Graz says: ‘Jensen and Buchwald clearly demonstrate that immersing a flow device into an ultrasound bath can prevent clogging problems that unfortunately are all too familiar to the flow/microreactor community.’

Direct Fluorination and Microreactor Technology

Elemental fluorine has long been considered to be too reactive and uncontrollable for use as a reagent in organic synthesis and this perception still predominates. Prof. Poliakoff’s comments on the popular Periodic Table video series (www.PeriodicVideos.com), ‘It was much more exciting than I thought …you see the flames,’ and general comments in standard advanced organic chemistry textbooks (J. March, Advanced Organic Chemistry, ‘Direct fluorination of aromatic rings with F₂ is not feasible at room temperature because of the extreme reactivity of F₂….not yet of preparative significance) are typical.

Despite this background, research into the use of elemental fluorine for organic synthesis at Durham has overcome the many problems of using fluorine gas for the safe synthesis of fine chemicals, in particular, by use of dilute fluorine gas in nitrogen, appropriate solvent choice (high dielectric constant media such as formic acid, sulfuric acid or acetonitrile), reactor vessel design, gas flow regulator systems and stainless steel/monel fluorine gas handling lines have developed over the years to allow selective direct fluorination of a range of aliphatic, dicarbonyl, aromatic, heteroaromatic, heterocyclic, steroid and carbohydrate derivatives to be established and the mechanism (regiochemistry, stereochemistry, selectivity, etc.) of these processes to be assessed. Indeed, direct fluorination of aromatic rings is feasible at room temperature ! Research expanding the use of fluorine gas continues to develop new selective fluorination methodology for the synthesis of a range of aromatic, heterocylic and aliphatic systems.^2,3

In particular, a process for the synthesis of a fluoroketoester first carried out in Durham was developed by our industrial collaborators, F2 Chemicals Ltd (UK), for the Pfizer company and forms a key starting material in the multi step synthesis of the widely used anti-fungal agent V-Fend (Voriconazole) throughout the clinical trial, launch and commercialization periods. In the period from January 2008 to March 2011 approximately 17 tonnes of the fluoroketoester were manufactured for Pfizer by F2 Chemicals Ltd. Global sales of V-Fend in the 2008-2010 period total $2.4 billion (Pfizer annual financial reports) and in 2010 was 17^th position in Pfizer’s best selling products and it is one of the global top 100 best selling pharmaceutical products.

Further reaction control in selective fluorination reactions was achieved by the design, fabrication and commissioning of single and multi-channel continuous flow reactor systems, establishing the use of convenient, inexpensive flow reactors for gas – liquid processes using flow regimes in the laboratory. Techniques for the supply of individual gas and liquid reagents from single sources to a parallel array of many flow channels at the same flow rate and pressure whilst maintaining laminar flow within the reactor channels and telescoped gas – liquid / liquid – liquid processes involving fluorination and ring formation in one continuous flow process have been developed.

References

Roughley, S. D.; Jordan, A. M. (2011). “The medicinal chemist’s toolbox: an analysis of reactions used in the pursuit of drug candidates”. J. Med. Chem. 54: 3451.
Dach, R.; Song, J. J.; Roschangar, F.; Samstag, W.; Senanayake, C. H. (2012). “The eight criteria defining a good chemical manufacturing process”. Org. Process Res. Dev. 16: 1697.
Trost, B. M. (1991). “The atom economy – a search for synthetic efficiency”. Science 254: 1471.
Van Aken, K.; Strekowski, L.; Patiny, L. (2006). “EcoScale, a semi-quantitative tool to select an organic preparation based on economical and ecological parameters”. Beilstein J. Org. Chem. 2 (No. 3).
Faucher, A-M.; Bailey, M. D.; Beaulieu, P. L.; Brochu, C.; Duceppe, J-S.; Ferland, J-M.; Ghiro, E.; Gorys, V.; Halmos, T.; Kawai, S. H.; Poirier, M.; Simoneau, B.; Tsantrizos, Y. S.; Llinas-Brunet, M. (2004). “Synthesis of BILN 2061, an HCV NS3 protease inhibitor with proven antiviral effect in humans”. Org. Lett. 6: 2901.
Yee, N. K.; Farina, V.; Houpis, I. N.; Haddad, N.; Frutos, R. P.; Gallou, F.; Wang, X-J.; Wei, X.; Simpson, R. D.; Feng, X.; Fuchs, V.; Xu, Y.; Tan, J.; Zhang, L.; Xu, J.; Smith-Keenan, L. L.; Vitous, J.; Ridges, M. D.; Spinelli, E. M.; Johnson, M. (2006). “Efficient large-scale synthesis of BILN 2061, a potent HCV protease inhibitor, by a convergent approach based on ring-closing metathesis”. J. Org. Chem. 71: 7133.
Zeng, X.; Wei, X.; Farina, V.; Napolitano, E.; Xu, Y.; Zhang, L.; Haddad, N.; Yee, N. K.; Grinberg, N.; Shen, S.; Senanayake, C. H. (2006). “Epimerization reaction of a substituted vinylcyclopropane catalyzed by ruthenium carbenes: mechanistic analysis”. J. Org. Chem. 71: 8864.
Grela, K.; Harutyunyan, S.; Michrowska, A. (2002). “A highly efficient ruthenium catalyst for metathesis reactions”. Angew. Chem. Int. Ed. 41: 4038.
Wei, X.; Shu, C.; Haddad, N.; Zeng, X.; Patel, N. D.; Tan, Z.; Liu, J.; Lee, H.; Shen, S.; Campbell, S.; Varsolona, R. J.; Busacca, C. A.; Hossain, A.; Yee, N. K.; Senanayake, C. H. (2013). “A highly convergent and efficient synthesis of a macrocyclic hepatitis C virus protease inhibitor BI 201302”. Org. Lett. 15: 1016.
Bornscheuer, U. T.; Huisman, G. W.; Kazlauskas, R. J.; Lutz, S.; Moore, J. C.; Robins, K. (2012). “Engineering the third wave of biocatalysis”. Nature 485: 185.
Savile, C. K.; Janey, J. M.; Mundorff, E. C.; Moore, J. C.; Tam, S.; Jarvis, W. R.; Colback, J. C.; Krebber, A.; Fleitz, F. J.; Brands, J.; Devine, P. N.; Huisman, G. W.; Hughes, G. J. (2010). “Biocatalytic asymmetric synthesis of chiral amines applied to sitagliptin manufacture”. Science 329: 305.
Desai, A. A. (2011). “Sitagliptin manufacture: a compelling tale of green chemistry, process intensification, and industrial asymmetric catalysis”. Angew. Chem. Int. Ed. 50: 1974.
Busacca, C. A.; Fandrick, D. R.; Song, J. J.; Sananayake, C. H. (2011). “The growing impact of catalysis in the pharmaceutical industry”. Adv. Synth. Catal. 353: 1825.
Johnson, M. D.; May, S. A.; Calvin, J. R.; Remacle, J.; Stout, J. R.; Dieroad, W. D.; Zaborenko, N.; Haeberle, B. D.; Sun, W-M.; Miller, M. T.; Brannan, J. (2012). “Development and scale-up of a continuous, high-pressure, asymmetric hydrogenation reaction, workup, and isolation”. Org. Process Res. Rev. 16: 1017.

EU and Australia link up on orphan drugs

April 9, 2014 4:44 am / Leave a comment

The European Medicines Agency (EMA) and Australia’s Therapeutic Goods Administration (TGA) have announced that they are to share the full assessment reports related to marketing authorisations (MA) for orphan drugs.

‘Shocking’ study gives hope to paralyzed people; shows electricity helps them stand, move legs

April 9, 2014 4:12 am / Leave a comment

Atasteofcreole's Blog

http://www.nydailynews.com/life-style/health/shocking-study-hope-paralyzed-people-article-1.1749234

‘It could still be a life-changer for them,’ experts say, but they also add that while this breakthrough is promising, ‘there is no miracle cure on the way’ for paralysis.

Electricity may provide hope to men and women who suffer paralysis.

Three years ago, doctors reported that zapping a paralyzed man’s spinal cord with electricity allowed him to stand and move his legs. Now they’ve done the same with three other patients, suggesting their original success was no fluke.

“This is wonderful news. Spinal cord injury need no longer be a lifelong sentence of paralysis,” said Dr. Roderic Pettigrew, director of the National Institute of Biomedical Imaging and Bioengineering, one of the National Institutes of Health, according to NBC News. “It is just downright marvelous.”

“The big message here is that people with spinal cord injury of the type these men had no longer need to think they have…

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Dacomitinib in phase 3 for lung (non-small cell) (NSCLC) Cancer

April 9, 2014 4:04 am / Leave a comment

Dacomitinib

(2E)-N-{4-[(3-Chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl}-4-(1-piperidinyl)-2-butenamide

4-Piperidin-1-yl-but-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-yl]-amide

1042385-75-0

pf299804…… pfizer

EGFR (HER1; erbB1) Inhibitors
HER4 (erbB4) Inhibitors
HER2 (erbB2) Inhibitors

Molecular formula:C24H25ClFN5O2
Molecular mass:469.95

Dacomitinib (PF-00299804) is an experimental drug candidate under development by Pfizer for the treatment of non-small-cell lung carcinoma. It is a selective and irreversible inhibitor of EGFR.^[1]

Dacomitinib has advanced to several Phase III clinical trials. The results of the first trials were disappointing, with a failure to meet the study goals,^[2]^[3]^[4] Additional Phase III trials are ongoing.^[2]

Dacomitinib is a HER (erbB) inhibitor in clinical trial development at Pfizer for the treatment of advanced non-small cell lung cancer (NSCLC) and for the treatment of relapsed/recurrent glioblastoma.

No recent development has been reported for research into the treatment of recurrent and/or metastatic head and neck squamous cell cancer. In 2012, Pfizer and SFJ Pharmaceuticals signed a codevelopment agreement for dacomitinib for the treatment of patients with locally advanced or metastatic NSCLC with activating mutations of epidermal growth factor receptor.

Substituted 4-phenylamino-quinazolin-6-yl-amides useful in the treatment of cancer have been described in the art, including those of U.S. Pat. No. 5,457,105 (Barker), U.S. Pat. No. 5,760,041 (Wissner et al.), U.S. Pat. No. 5,770,599 (Gibson), U.S. Pat. No. 5,929,080 (Frost), U.S. Pat. No. 5,955,464 (Barker), U.S. Pat. No. 6,251,912 (Wissner et al.), U.S. Pat. No. 6,344,455 (Bridges et al.), U.S. Pat. No. 6,344,459 (Bridges et al.), U.S. Pat. No. 6,414,148 (Thomas et al.), U.S. Pat. No. 5,770,599 (Gibson et al.), U.S. patent application 2002/0173509 (Himmelsbach et al.), and U.S. Pat. No. 6,323,209 (Frost).

Dacomitinib is a pan-human epidermal growth factor receptor (pan-HER) inhibitor developed by Pfizer, as ー small molecules targeting ffiR-1, HER-2 and HER-4 tyrosine kinase inhibitor by irreversibly binding to HER-l, HER-2, HER-4 and anti-tumor effect. Ni-line treatment of non-small cell lung cancer (NSCLC) display, Dacomitinib in non-small cell lung cancer Dinner erlotinib compared to some extend on progression-free survival and quality of life have mentioned the smell.

_4] Structural formula for Dacomitinib

[0005] U.S. patent US7772243 Dacomitinib first proposed a synthesis method, first, a fluorine-2_ _4_ amino acid and formamidine ring closure reaction to give 7 – fluoro-4 – quinazolinone, nitration and then successively chlorination reaction, to give 4 – chloro-7 – fluoro-6 – nitro-quinazoline; another aspect ー 3 – chloro-4 – amino-substituted on a fluoroaniline to give 3 – chloro – # – (3,4 – ni section yl methoxy)-4_ fluoro-aniline, obtained after the coupling of both an amino-protected N-(3 – chloro-4 – fluorophenyl)-7 – fluoro-6 – nitro-quinazoline -4 – amine, protected amino N-(3 – chloro-4 – fluorophenyl

Yl)-7_ fluoro-6 – nitro-quinazolin-4 – amine is of formula

Followed by a methoxy group, an amidation reaction and hydrogenation, the final deprotection ko under the action of trifluoroacetic acid to give the final product Dacomitinib. Throughout the reaction as follows:

synthesis

http://www.google.com/patents/CN103304492A?cl=en

Synthesis ー kind EGFR inhibitors Dacomitinib, synthetic route for

A synthetic method EGFR inhibitors Dacomitinib, concrete steps are as follows:

Step I, 7 – fluoro-4 – Synthesis of quinazolinone:

30 g (0.1934mol) 2 – fluoro-amino acid was dissolved in 250 ml _4_ formamide among the reaction was heated to 150 ° C for 6 inch, TLC plates to determine the point of completion of the reaction. The reaction was poured hot into 2000 ml of ice water, filtered, the filter cake was washed with water, vacuum dried at 50 ° C for 14 hours to give a pale brown solid powder 7 – fluoro-4 – quinazolinone, 28 g, yield 88%.

[0021] 2 walk 7 – fluoro-6 – nitro-4_ (hydrogen) _ Synthetic quinazolinones of:

Concentrated sulfuric acid (50 ml) and fuming nitric acid (50 ml) mixture was cooled with an ice bath to (TC hereinafter under stirring slowly added 25 g (0.1523mol) 7 – fluoro-4 – quinazolinone , the addition was complete, the reaction mixture was stirred at room temperature for I hour and then the reaction was heated to 110 ° C for 2 inch, TLC plates to determine the point of completion of the reaction the reaction was cooled to room temperature, 300 ml of ice water, the precipitated solid was stirred for 30 minutes , filtered, the filter cake was washed with water, vacuum dried at 50 ° C in 14 hours to give a yellow solid powder 7 – fluoro-6 – nitro-4 – (hydrogen) – quinazolinone, 26 g, yield 82%.

[0022] Step 3 6 – amino-7 – fluoro-4 – (hydrogen) – quinazolinone Synthesis:

24 g (0.1148mol) 7 – fluoro-6 – nitro _4_ (hydrogen) – quinazolinone was dissolved in 400 ml of methanol was added 2 g of palladium / carbon catalyst was added 8 ml of concentrated hydrochloric acid, and hydrogen was 2 small inch atmospheric reaction, TLC plates to determine the point of the reaction is complete. The catalyst was removed by suction filtration through celite, washed several fitness methanol, and the filtrate was concentrated by rotary evaporation to dryness to give 6 – amino-7_ fluoro-4 – (hydrogen) – quinazolinone, yellow powder, 20 g, yield 97%.

[0023] 4 walk, ⑶ -4 – (piperidin – Suites yl) -2 – butene acid methyl ester synthesis:

18 g (0.1006mol) 4 – bromo-methyl crotonate dissolved in 180 ml of methylene chloride ni added 27.9 g (0.2019mol) potassium carbonate, cooled to ice-bath (TC, was slowly added dropwise 10 ml (0.1012mol ) piperidine, (I reaction was stirred under a small inch TC, TLC plates to determine the point of completion of the reaction was concentrated by rotary evaporation to dryness, to give (E) -4 – (piperidin-1 – yl) – 2 – butenoic acid methyl Cool as a yellow solid, 17.1 g, yield 93%.

[0024] 5th walk, Buddhist) -4 – (piperidin-1 – yl) -2 – butene acid hydrochloride synthesis:

16 g (0.0873mol) of W) -4 – (piperidin-_1_ yl) -2 – butenyl acetate and 80 ml of concentrated hydrochloric acid was added to 250 ml of 1,4 – ni oxygen dioxane, heated under reflux 20 hours inch, TLC plate point the reaction was determined complete, the reaction solution was concentrated by rotary evaporation to dryness surplus was recrystallized from isopropanol to give a pale yellow solid, Buddhist) _4-(piperidin-1 – yl) -2 – butene acid hydrochloride, 14.5 g, yield 81%.

[0025] Step 6, (E) -4 – (piperazine Jie fixed -1 – yl) – 2 – butenyl chloride synthesis:

13 g (0.0632mol) of (K) ~ 4 ~ (piperidin-1 – yl) -2 – butene acid hydrochloride was dissolved in 750 ml of methylene chloride ni, 5 ml of DMF, was slowly added dropwise 8 ml ( 0.0933mol) of oxalyl chloride, the reaction was stirred at room temperature for I h, TLC plates to determine the point of completion of the reaction, the reaction solution was concentrated to dryness by rotary evaporation to give a pale yellow oil, Buddhist) _4-(piperidin-1 – yl) -2 – butyl allyl chloride, 11.8 g, yield 99%.

[0026] Step 7 (cargo) – # – (7 – fluoro-4 – oxo-3 ,4 – ni hydrogen quinazolin-6 – yl) -4 – (piperidin-1 – yl) -2 – butene amide Synthesis:

11 g (0.0586mol) of the) -4 – (piperidin-1 – yl) – 2 – butenyl chloride ni chloride (50 ml) was slowly added dropwise to 6 – amino-1 – fluoro-4 – ( hydrogen) – quinazolinone (7 g, 0.0391mmol), three ko amine (14 ml) and the mixture was ni chloride (200 ml), the reaction mixture was stirred at room temperature for 2 hours the reaction inch, TLC determined the completion of reaction points board , was added 800 liters of halo ni halo chloroformate and 500 liters of burning the separated organic phase was washed with 500 liters of halo, halo and then with 500 liters of brine, dried over magnesium sulfate, and concentrated by rotary evaporation to dryness was subjected to silica gel surplus Column chromatography (30% acid ko ko acetate / hexane) to give (M)-N-(7 – fluoro-4 – oxo-3 ,4 – ni hydrogen quinazolin-6 – yl) -4 – (piperidin-1 – yl) -2 – butenamide, as a pale yellow solid, 12.3 g, yield 95%.

Step 8 [0027] (2 ^) – # – (7 – methoxy – 4 – oxo _3, 4_ ni hydrogen quinazolinyl _6_ yl)-4_ (piperidin-1 – yl) – Synthesis 2_ butenamide:

I ^ xN MeONa N. Under nitrogen atmosphere, to 100 ml of anhydrous methanol was slowly added 1.52 g of sodium metal (0.0661mol), stirred for 10 minutes to dissolve all of the sodium metal to the completion of the reaction, to obtain a freshly prepared solution of sodium methoxide, and the The sodium methoxide solution was added 11 g (0.0333mol) of (receive) (7 – fluoro-4 – oxo-3 ,4 – ni hydrogen quinazolin-6 – yl) -4 – (piperidin-1 – yl) 2_ butene-amide, the reaction was heated to reflux for 3 inch, TLC plates to determine completion of the reaction point, cooled to room temperature, acidified with 2N hydrochloric acid solution to pH = 3 ~ 4, and concentrated by rotary evaporation to dryness, the residue was washed with water beating, filtration, The filter cake was washed with water, vacuum dried at 50 ° C in 14 hours to give (article) – # – (7 – methoxy – 4 – oxo – ni hydrogen quinazolin-6 – yl) – 4_ (piperidin-1 – yl)-2_ butenamide yellow solid, 10.6 g, yield 93%.

[0028] Step 9, {W,-N-(4 – chloro-7 – methoxy-quinazoline _6_ yl)-4_ (piperidin _1_ yl)-amide <EMI butene 2_:

9 g (0.0263mol) of (receive) – # – (7 – methoxy _4_ oxo – ni hydrogen quinazolin-6 – yl)-4_ (piperidin-1 – yl) – 2_ butenamide were added to 40 ml of phosphorus oxychloride was heated under reflux for 2 inch, TLC plates to determine the point of completion of the reaction, the reaction solution was concentrated to dryness by rotary evaporation, ice water was added surplus, beating, filtered, the cake washed with washed with water, vacuum dried at 50 ° C in 14 hours to give {W,-N-(4 – chloro-7 – methoxy-quinazolin-6 – yl) -4 – (piperidin-1 – yl) – 2 – butene amide as a yellow solid, 7 g, yield 74%

(2E)-N-(4 – chloro-7 – methoxy-quinazolin-6 – yl) -4 – (piperidin-1 – yl) -2 – butene amide (6 g,

0.0166mol), 3 – chloro-4-fluoro-aniline (2.6 g, 0.0179mol) and three ko amine (2.6 ml, 0.0186mol) was added to 140 ml of isopropanol and the reaction was heated to reflux for 3 inch, TLC plates to determine the point completion of the reaction, cooled to room temperature, filtered, the filter cake washed with methanol, vacuum dried at 50 ° C in 14 hours to give the final product Dacomitinib, a yellow solid, 6.6 g, yield 84%.

/////////////////////////

synthesis

US7772243
http://www.google.com/patents/US7772243

Scheme 1, wherein the 4-position aniline group is represented a 4-fluoro-3-chloro aniline group.

4-Chloro-7-fluoro-6-nitroquinazoline (7) can be prepared by methods similar to those described in J.Med. Chem. 1996, 39, 918-928. Generally, 2-amino-4-fluoro-benzoic acid (1) can be reacted with formamidine (2) and acetic acid (3) in the presence of 2-methoxyethanol to provide 7-Fluoro-3H-quinazolin-4-one (4). The 7-fluoro-3H-quinazolin-4-one (4) can be nitrated to 7-fluoro-6-nitro-3H-quinazolin-4-one (5), which can be treated with thionyl chloride to yield 4-chloro-6-nitro-7-fluoro-3H-quinazoline (6). The 4-chloro-quinazoline compound (6) can be combined with a desirably substituted aniline, represented above by 4-fluoro-3-chloro-aniline, in the presence of a tertiary amine and isopropanol to provide the 4-anilino-6-nitro-7-fluoro-quinazoline (7).

The 4-anilino-6-nitro-7-fluoro-quinazoline (7) may be reacted with an alcohol of the formula R₃OH, wherein R₃is as defined above, to yield the 7-alkoxylated compound (8). Reduction of the 6-nitro compound (8) provides the 6-amino analog (9).

The 6-position amino compound (9) may be reacted with a haloalkenoyl chloride (12), such as a 4-bromo-but-2-enoyl chloride, 5-bromo-pent-2-enoyl chloride, 4-chloro-but-2-enoyl chloride, or 5-chloro-pent-2-enoyl chloride, to provide an alkenoic acid[4-anilino]-7-alkoxylated-quinazolin-6-yl-amide (13). Haloalkenoyl chloride agents useful in this scheme may be prepared by methods known in the art, such as the treatment of a relevant haloalkenoic acid, represented by bromoalkenoic acid ester (10), with a primary alcohol, yielding the corresponding haloalkenoic acid (11), which may in turn be treated with oxalyl chloride to provide the desired haloalkenoyl chloride (12).

Finally, the quinazoline-6-alkanoic acid compound (13) may be treated with a cyclic amine, such as piperidine, piperazine, etc., to provide the desired final compound (14).

EXAMPLE 2

4-Piperidin-1-yl-but-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-yl]-amide (Synthetic Route No. 1)

The title compound and other 7-methoxy analogs of this invention can be prepared as described in Example 1 by replacing the 2-fluoroethanol used in Example 1 with stoichiometric amount of methanol.

EXAMPLE 3 4-Piperidin-1 -yl-but-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-7-methoxv -quinazolin-6-yl]-amide (Synthetic Route No. 2)

An alternative synthetic route for compounds of this invention involves preparing the 6-position substituent chain as a Het-alkenoyl chloride as depicted in Scheme 2, below.

It will be understood that other compounds within this invention may be prepared using Het-butenoyl halide, Het-pentenoyl halide and Het-hexenoyl halide groups of the formula:

wherein R₄is as described herein and halo represents F, Cl, Br or I, preferably Cl or Br. One specific group of these Het-alkenoyl halides includes those compounds in which halo is Cl or Br, R₄is —(CH₂)_m-Het, m is an integer from 1 to 3, and Het is piperidine or the substituted piperidine moieties disclosed above.

EXAMPLE 4 4-Piperidin-1-yl-but-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-yl]-amide (Synthetic Route No. 3)

3-Chloro-4-fluoro-phenylamine 15 (50.31, 345.6 mmole) and 3,4-Dimethoxy-benzaldehyde 16 (57.43 g, 345.6 mmole) were mixed in 500 ml of IPA and cooled in an ice-water. The glacial acetic acid was added (20.76 g, 345.6 mole) and then sodium cyanoborohydride in one portion. The reaction was stirred at room temperature (RT) for 24 hrs. 250 mL of 10% NaOH was added dropwise at RT after the reaction was completed. The mixture was stirred for ½ hr. The slurry was then filtered and washed with IPA and dried in vacuo. The mass weight 88.75 g (17, 87%).

Compounds 6 (3 g, 13.18 mmole) and 17 (3.9 g, 13.18 mmole) were combined in CH₃CN (25 mL) and heated for one hr. Mass spectroscopy indicated no starting material. Saturated K₂CO₃was added and the reaction was extracted 3× with EtOAc. The organic layers were combined, washed with brine and concentrated in vacuo to give 6.48 g of 7 (78.4%).

Compound 7 (72.76 g, 149.4 mmole) was added to a cool solution of NaOMe in 1.5 L of dry MeOH under N₂. The cooling bath was removed and the mixture was heated to reflux and stirred for 1 hr. The reaction was cooled to room temperature and quenched with water until the product precipitated out. The solid was filtered and washed with water and hexanes. The product was slurred in refluxing EtOAc and filtered hot to provide 68.75 g of yellow soled 8 (73%).

Compound 8 (63.62 g, 127.5 mole) was hydrogenated using Raney/Ni as catalyst to obtain 43.82 g of 9 (100%). Oxalyl chloride (6.5 g, 51.18 mmole) was added slowly to a suspension of 13 (10.5 g, 51.2 mmole) in 200 ml of dichloromethane containing 8 drops of DMF, after the reaction become homogeneous, the solvent was removed and the residual light yellow solid was slurred in 200 ml of DMAC and 9 (20 g, 42.65 mmole) was added gradually as a solid. The reaction was stirred for 15 min. and poured slowly into 1N NaOH. The mixture was extrated 3× EtOAc. The combined organic layers were washed with brine, filtered and concentrated in vacuo to obtain 28.4 g (100%) 10.

Compound 10(13.07 g, 21.08 mmole) was dissolved in trifluoroacetic acid (TFA) (74 g, 649 mmole) and heated to 30° C. for 24 hrs. The reaction was cooled to RT and poured gradually into a cooled 1 N NaO H-brine solution. Precipitate formed and was filtered and washed with 3X water then dried. The precipitate was recrystallized from toluene to obtain pure 4-Piperidin-1-vl-but-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino) -7-methoxv-puinazolin-6-yl]-amide (9.90 g, 89%).

Example 1 is similar but not same…caution

EXAMPLE 1 4-Piperidin-1-yl-but-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-7-(2-fluoro-ethoxy)-quinazolin-6-yl]-amide

7-fluoro-6-nitro-4-chloroquinazoline (14.73,g, 65 mmol) was combined with 3-choro-4-fluoroaniline (9.49 g, 65 mmol) and triethylamine (10 mL, 72 mmol) in 150 mL of isopropanol. The reaction was stirred at room temperature for 1.5 hours, resulting in a yellow slurry. The solid was collected by filtration, rinsing with isopropanol and then water. The solid was dried in a 40° C. vacuum oven overnight to give 19.83 g (91%) of the product as an orange solid.

MS (APCI, m/z, M+1): 337.0

NaH (60% in mineral oil, 3.55 g, 88 mmol) was added, in portions, to a solution of 2-fluoroethanol (5.19 g, 80 mmol) in 200 mL THF. The reaction was stirred for 60 minutes at room temperature. To the reaction was added 7-fluoro-6-nitro-4-(3-chloro-4-fluoroaniline)quinazoline (18.11 g, 54 mmol) as a solid, rinsing with THF. The reaction was heated to 65° C. for 26 hours. The reaction was cooled to room temperature and quenched with water. THF was removed in vacuo. The resulting residue was sonicated briefly in water then the solid collected by filtration. The solid was triturated with MeOH, filtered and dried in a 40° C. vacuum oven overnight to 12.63 g of the product. Additional product was obtained by concentrating the MeOH filtrate to dryness and chromatography eluting with 50% EtOAc/hex. The isolated material was triturated with MeOH (2×), filtered and dried. 3.90 g

Total yield: 16.53 g, 81%

MS (APCI, m/z, M+1): 381.0

7-(2-fluoroethoxy)-6-nitro-4-(3-chloro-4-fluoroaniline)quinazoline (0.845 g, 2.2 mmol) in 50 mL THF was hydrogenated with Raney nickel (0.5 g) as the catalyst over 15 hours. The catalyst was filtered off and the filtrate was evaporated to give 0.77 g of product. (99%)

MS (APCI, m/z, M+1): 351.2

Methyl 4-bromocrotonate (85%, 20 mL, 144 mmol) was hydrolyzed with Ba(OH)₂in EtOH/H₂O as described in J.Med.Chem. 2001, 44(17), 2729-2734.

MS (APCI, m/z, M−1): 163.0

To a solution of 4-bromocrotonic acid (4.17 g, 25 mmol) in CH₂Cl₂(20 mL) was added oxalyl chloride (33 mL, 38 mmoL) and several drops of DMF. The reaction was stirred at room temperature for 1.5 hours. The solvent and excess reagent was removed in vacuo. The resulting residue was dissolved in 10 mL THF and added to a 0° C. mixture of 6-amino-7-(2-fluoroethoxy)-4-(3-chloro-4-fluoroaniline)quinazoline (5.28 g, 15 mmol) and triethylamine (5.2 mL, 37 mmol). The reaction was stirred at 0° C. for 1 hour. Water was added to the reaction and the THF removed in vacuo. The product was extracted into CH₂Cl₂(400 mL). The organic layer was dried over MgSO₄, filtered and concentrated. The crude material was chromatographed on silica gel eluting with 0-4% MeOH/CH₂Cl₂. An isolated gold foam was isolated. Yield: 4.58 g, 61%

MS (APCI, m/z, M−1): 497.1

Piperidine (0.75 mL, 6.7 mmol) was added to a solution of the above compound (3.35 g, 6.7 mmol) and TEA (2.80 mL, 20 mmol) in 10 mL DMA at 0° C. The reaction was stirred at 0° C. for 17 hours. Water was added to the reaction until a precipitate was evident. The reaction was sonicated for 40 minutes and the liquid decanted. The residue was dissolved in CH₂Cl₂, dried over MgSO₄, filtered and concentrated. The material was chromatographed on silica gel eluting with 4-10% MeOH/CH₂Cl₂. The isolated residue was triturated with acetonitrile (2×) and collected by filtration. Impurity found: Michael addition of piperidine (2.2% in first trituration of acetonitrile). Additional material can be obtained from the acetonitrile filtrates.

Yield: 0.95 g, 27%

MS (APCI, m/z, M+1): 502.3

……………

US 20050250761 A1,

References

“Dacomitinib”. NCI Drug Dictionary.
Zosia Chustecka (January 27, 2014). “Dacomitinib Fails in Pretreated Non-small Cell Lung Cancer”. Medscape.
“Blow to Pfizer as dacomitinib fails in lung cancer trials”. pmlive.com. 28th January 2014.
“Pfizer Announces Top-Line Results From Two Phase 3 Trials Of Dacomitinib In Patients With Refractory Advanced Non-Small Cell Lung Cancer”. Pfizer Press Release. January 27, 2014.
Tyrosine kinase inhibitors.17. Irreversible inhibitors of the epidermal growth factor receptor: 4-(Phenylamino)quinazoline- and 4-(phenylamino)pyrido[3,2-d]pyrimidine-6-acrylamides baring additional solubilizing functions
J Med Chem 2000, 43(7): 1380

Dacomitinib Fact Sheet, Pfizer

WO1996033980A1 *	23 Apr 1996	31 Oct 1996	Keith Hopkinson Gibson	Quinazoline derivatives
WO1997038983A1 *	8 Apr 1997	23 Oct 1997	Alexander James Bridges	Irreversible inhibitors of tyrosine kinases
WO2002050043A1 *	12 Dec 2001	27 Jun 2002	Boehringer Ingelheim Pharma	Quinazoline derivatives, medicaments containing said compounds, their utilization and method for the production thereof
WO2004069791A2 *	3 Feb 2004	19 Aug 2004	Hubert Gangolf Klemens Barth	Preparation of substituted quinazolines
US5760041 *	21 Jan 1997	2 Jun 1998	American Cyanamid Company	4-aminoquinazoline EGFR Inhibitors

13C NMR OF SIMPLE MOLECULES…………..Brush up….???

April 8, 2014 2:14 pm / 1 Comment on 13C NMR OF SIMPLE MOLECULES…………..Brush up….???

ما هو هذا، لماذا أنت قلق، فرشاة مع الأشياء البسيطة، وسوف يخرج عبقري، وتعلم معي، قطرات صغيرة من الماء جعلالمحيطات، وسوف يكون خبيرا في هذا

what is this, why are you worried, brush up with simple things, you will come out genius, learn with me, small drops of water make an ocean, you will be an expert in this

あなたが心配している理由は、これは簡単なことでブラッシュアップ、、何か、あなたは、天才が出てくる私と一緒に学ぶことが、水の小さな滴が海を作るには、この専門家になる

structure

Name: 1,2-dimethoxymethane

C₄H₁₀O₂

From the molecular formula, the compound has “0 degrees of unsaturation” (no double bonds or rings).

C13 Spectrum

The ¹³C NMR has two peaks, a quartet at 54 (a CH₃) and a triplet at 80 (a CH₂). Since the molecule has four carbons and only two ¹³C NMR peaks, there must be symmetry. Both peaks are in the regions where carbons next to electronegative atoms occur (oxygen).

τι είναι αυτό, γιατί είσαι ανήσυχος, βούρτσα με απλά πράγματα, θα βγει ιδιοφυΐα, να μάθουν μαζί μου, μικρές σταγόνες του νερού κάνει έναν ωκεανό, θα είστε ένας εμπειρογνώμονας σε αυτό

আপনি চিন্তিত কেন এই সহজ জিনিস নিয়ে ব্রাশ,, কি, আপনি, প্রতিভা বাইরে আসতে আমার সাথে শিখতে হবে, জলের ছোট ঝরিয়া একটি মহাসাগর না, আপনি এই একজন বিশেষজ্ঞ হতে হবে

C₅H₇O₂N

From the molecular formula, the compound has “3 degrees of unsaturation” (3 double bonds or rings).

structure

: ethyl cyanoacetate

C13 Spectrum

The ¹³C NMR has 5 peaks, a quartet at 14 (a CH₃), a triplet at 59 (a CH₂), another triplet at 22 (another CH₂), and two singlets, one at 118 and one at 172. Since the molecule has five carbons and five ¹³C NMR peaks, there must be no symmetry. The singlet at 172 is in the carbonyl region, most likely an acid or an ester. The CH₂ at 59 is in the region where carbons next to electronegative atoms occur (i.e., oxygen) and the CH₃ at 14 is a simple terminal methyl, suggesting an -O-CH₂CH₃ residue. The singlet at 118 would be consistent with a nitrile carbon and the shielded CH₂ at 22 suggests that it may be adjacent to the sp-carbon of the nitrile

מה זה, למה אתה מודאג, לרענן עם דברים פשוטים, אתה תצא גאון, ללמוד איתי, טיפות קטנות של מיםיגרמו לים, אתה תהיה מומחה בזה

C₆H₁₀OFrom the molecular formula, the compound has “2 degrees of unsaturation” (2 double bonds or rings).

C13 Spectrum

structure

2-butanon-4-ene

The ¹³C NMR has 6 peaks, a quartet at 25 (a CH₃), a triplet at 49 (a CH₂), another quartet at 17 (another CH₃), two doublets (a CH) , one at 124 and one at 131, and one singlet at 207. Since the molecule has six carbons and six ¹³C NMR peaks, there must be no symmetry. The singlet at 207 is in the carbonyl region, most likely an aldehyde or ketone. The CH₃ groups at 17 and 25 are consistent with simple terminal methyl groups, with one slightly shifted by an mildly electronegative group (a carbonyl?). The doublets at 124 and 131 are in the alkene region, suggesting a -CHCH- group. The remaining CH₂ group at 49 is probably deshielded by two electronegative groups.

o que é isso, por que você está preocupado, retocar com coisas simples, você vai sair gênio, aprender comigo, pequenas gotas de água fazem um oceano, você vai ser um especialista neste

C₈H₈O

From the molecular formula, the compound has “5 degrees of unsaturation” (5 double bonds or rings).

structure

acetophenone

C13 Spectrum

The ¹³C NMR has 6 peaks, a quartet at 27 (a CH₃), three doublets (CH groups), at 129, 128 and 133, and two singlets, one at 137 and one at 197. Since the molecule has eight carbons and six ¹³C NMR peaks, there must some degree of symmetry. The singlet at 197 is in the carbonyl region, most likely an aldehyde or ketone. The CH₃ groups at 27 is consistent with a simple terminal methyl group, slightly shifted by an mildly electronegative group (a carbonyl?). The doublets at 129, 128 and 133 and the singlet at 137 are in the aromatic region, suggesting a monosubstituted aromatic group, with symmetry in four of the six carbons.

நீங்கள் கவலை ஏன் இந்த எளிய பொருட்களை கொண்டு துலக்க, என்ன, நீங்கள், மேதை வெளியே வர எனக்கு கற்று, நீர் சிறு துளிகள் ஒரு கடல் செய்ய, நீங்கள் இந்த ஒரு நிபுணர் இருக்கும்

के तपाईं चिंतित हो किन यो सरल कुरा संग ब्रश,, के हो, तपाईं, प्रतिभा बाहिर आउन मलाई संग सिक्न हुनेछ, पानी सानो थोपा एक महासागर बनाउन, तपाईं यस मा एक विशेषज्ञ हुनेछ\

તમને ચિંતા થતી હોય કે શા માટે આ સરળ બાબતો સાથે બ્રશ, શું છે, તમે પ્રતિભા બહાર આવે મારી સાથે શીખશે, પાણી નાના ટીપાં સમુદ્ર કરો, તો તમે આ એક નિષ્ણાત હશે

kas tas ir, kāpēc jūs uztraucaties, suka ar vienkāršām lietām, jūs iznākt ģēnijs, mācīties kopā ar mani, nelieli ūdens pilieni veikt okeānu, jums būs eksperts šajā

что это такое, почему ты беспокоишься, освежить с простых вещей, вы будете выходить гений, узнать со мной, маленькие капли воды сделать океан, вы будете экспертом в этом

hvað er þetta, af hverju ert þú áhyggjur, bursta upp með einföldum hlutum, verður þú að koma út snillingur, læra með mér, litla dropa af vatni gera haf, verður þú að vera sérfræðingur í þessu

C₆H₈OFrom the molecular formula, the compound has “3 degrees of unsaturation” (3 double bonds or rings).

structure

cyclohexanon-2-ene

The ¹³C NMR has 6 peaks, three triplets (CH₂ groups) at

46, 30 and 41, two doublets (CH groups), at

129 and 145, and one singlet at

198. Since the molecule has six carbons and six ¹³C NMR peaks, there must be no symmetry. The singlet at

198 is in the carbonyl region, most likely an aldehyde or ketone. Two of the three CH₂ groups are shifted by electronegative groups, suggesting a X-CH₂-CH₂-CH₂-Y unit. The doublets at

129 and 145 are in the alkene region, suggesting a -CH

CH- group. The three degrees of unsaturation suggests that the molecule also has a ring.

这是什么，你为什么担心，刷了简单的事情，你会出来的天才，学我，小水珠做出的海洋，你将在这方面的专家

당신이 걱정하는 이유는 간단한 것들로 브러시, 무엇인가, 당신은 천재 나올 나와 함께 배울 것, 물 작은 방울은 바다를 만들어,이 분야의 전문가가 될 것입니다

Electronegative groups are “deshielding” and tend to move NMR signals from attached carbons further “downfield” (to higher ppm values).
The -system of alkenes, aromatic compounds and carbonyls strongly deshield C nuclei and move them “downfield” to higher ppm values.
Carbonyl carbons are strongly deshielded and occur at very high ppm values. Within this group, carboxylic acids and esters tend to have the smaller values, while ketones and aldehydes have values 200.

The ¹³C chemical shift is dependent both on the presence of electronegative groups and on the steric environment. This is best demonstrated by examining a variety of hexane isomers:

Simple interior (primary and secondary) carbons tend to be in the range 25 – 45. Methyl groups which terminate unbranched alkyl chains, however, are significantly shielded (moved to lower values), as shown by the examples above ( 14, 14.3 and 8.7). The origin of this effect is thought to be steric compression in the gamma () position due to gauche interactions. This is shown schematically below and the gamma position is marked above in the example for hexane.

The presence of an electronegative atom such as oxygen tends to move the chemical shift of the Œ-carbon down into the region 65 – 90, as shown in the examples below:

Halogens, however, have effects which are difficult to predict and carbons adjacent to halogens tend to have chemical shifts in the 30 – 50 region, as shown below. The effects are not simply additive, however, and multiple substitution can often be shielding (move the signal to lower values). The nitrile carbon is significantly shielding and adjacent carbons tend to occur in the 20 – 25 region.

Alkene carbons tend to have chemical shifts in the range 110 – 140, as shown in the examples below. Conjugation between alkene centers has little effect, as demonstrated by the two middle structures shown below. Conjugation with an oxygen, however, has a dramatic shielding effect, which is attributed to contributions from the resonance forms shown below.

Alkyne carbons occur in the region 65 -85, and are significantly shielding to the carbons which are immediately adjacent ( 1.5 for the terminal methyl of 2-pentyne).

Carbonyls are the most highly deshielded carbons which are typically encountered. Their intensity is usually weak, since there are no attached hydrogens to contribute to the Nuclear Overhauser Effect enhancement (with the exception of aldehydes). Typical chemical shifts occur in the region 170 – 210 with esters, carboxylic acids and amides at the low end, and simple ketones and aldehydes at the high end of the range.

Aromatic carbons have chemical shifts in the range 120 – 140 and are shifted within this range by the nature of the attached substituent. The multiplicity of aromatic peaks in the non-decoupled spectrum is useful for identifying aromatic substitution patterns.

آپ پریشان کیوں ہیں اس سادہ چیزوں کے ساتھ برش،، کیا ہے، آپ، ہوشیار باہر آ میرے ساتھ سیکھ جائے گی، پانی کے چھوٹے چھوٹے قطرے ایک سمندر بنانے کے لئے، آپ کو اس میں ایک ماہر ہو جائے گا

THANKS AND REGARD’S
DR ANTHONY MELVIN CRASTO Ph.D

amcrasto@gmail.com

MOBILE-+91 9323115463

GLENMARK SCIENTIST , INDIA
web link

ABOUTME

BRAND ANTHONYCRASTO

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1H NMR OF SIMPLE MOLECULES.. Brush up

April 8, 2014 10:43 am / 1 Comment on 1H NMR OF SIMPLE MOLECULES.. Brush up

what is this, why are you worried, brush up with simple things, you will come out genius, learn with me, small drops of water make an ocean, you will be an expert in this

structure

4-methylbenzaldehyde

NMR Spectrum

The proton NMR has three peaks; a singlet at 2.2 (3H), and a singlet at 10 (1H) and two doublets centered around 7.6. The doublets centered at 7.6 are in the aromatic region; the fact that two doublets are observed (2H each) suggests a 1,4-disubstituted aromatic compound.

The peak at 2.2 is in the region for a methyl group adjacent a mildly electronegative group. The singlet at 10 is in the region observed for aldehydic protons. The presence of two doublets in the aromatic region is highly characteristic of 1,4-disubstitution.

structure

methyl acetate (methyl ethanoate)

NMR Spectrum

The proton NMR has two singlets of equal area. The fact that the molecule has 6 hydrogens means that there must be two non-identical CH₃ groups in the molecule and that they are non-adjacent. The peak at 1.95 is in the area generally observed for methyl groups adjacent to carbonyls; the peak at 3.85 is in the region for methyl groups adjacent to electronegative atoms, i.e., oxygen.

structure
diethyl ketone (3-pentanone)

NMR Spectrum

The proton NMR has a quartet and a triplet, indicating a CH₂ adjacent to a CH₃. The peak at 2.5 is in the area generally observed for methyl groups adjacent to mildly electronegative groups; the peak at 1.2 is in the region for simple methyl groups adjacent to carbons (CH₃CH₂). The molecule contains oxygen, but the peak at 2.5 is not shifted enough for this to represent an -O- linkage, so it must represent a carbonyl.

structure

acetaldehyde (ethanal)

NMR Spectrum

The proton NMR has two peaks; at high resolution, fine coupling is evident between them (J 1 Hz) with the peak at 9.7 being a quartet and the peak at 2.1 being a doublet, indicating a CH coupled to a CH₃. The peak at 9.7 is in the area generally observed for aldehydic protons; the peak at 2.1 is in the region for a methyl group adjacent a carbonyl. The molecule contains oxygen, but the peak at 2.1 is not shifted enough for this to represent an -O- linkage, so it must represent a carbonyl. The very small coupling constant suggests that the proton and the CH₃ group are not immediately adjacent, but that this represents an example of cross-space coupling.

o que é isso, por que você está preocupado, retocar com coisas simples, você vai sair gênio, aprender comigo, pequenas gotas de água fazem um oceano, você vai ser um especialista neste

structure

Name: ethyl acetate (ethyl ethanoate)

NMR Spectrum

The proton NMR has three peaks; a quartet at 4.1 (2H), a triplet at 1.2 (3H) and a singlet at 1.97 (3H). The quartet and triplet suggest a CH₂ coupled to a CH₃ in an ethyl group. The peak at 4.1 is in the area generally observed for CH groups adjacent to electronegative groups, i.e., oxygen. The peak at 2 is in the region for a methyl group adjacent a carbonyl.

kas tas ir, kāpēc jūs uztraucaties, suka ar vienkāršām lietām, jūs iznākt ģēnijs, mācīties kopā ar mani, nelieli ūdens pilieni veikt okeānu, jums būs eksperts šajā

methyl vinyl ether (methyl ethenyl ether)

The proton NMR has four groups of peaks; the singlet at

3.6 (3H) is consistent with an isolated CH₃ group adjacent to an electronegative center, such as oxygen. The sets of highly split doublets centered at

6.5, 4.2 and 4.0 (there is overlap of these at

4.1) span the region where alkene hydrogens are observed. The complex splitting pattern observed resembles an ABC pattern for a terminal alkene.

这是什么，你为什么担心，刷了简单的事情，你会出来的天才，学我，小水珠做出的海洋，你将在这方面的专家

Name: 1,2-dimethoxyethane

The proton NMR has two peaks; both singlets are consistent with isolated groups adjacent to an electronegative center, such as oxygen. The fact that the molecule contains ten hydrogens, but only shows singlets for two and three hydrogens requires a great deal of symmetry in the molecule, i.e., both CH₃ groups must be identical, as must both CH₂ groups.

4-isopropyl-1-methoxybenzene (4-(1-methylethyl)-1-methoxybenzene)

The proton NMR has four sets of peaks; a singlet at

3.6 (3H), two sets of doublets centered around

6.9 (4H), a septet at

2.7 (1H) and a doublet at

1.6. The singlet at

3.6 is consistent with an isolated CH₃adjacent to an electronegative center, such as an oxygen. The septet and doublet strongly suggest an isopropyl group

CH(CH₃) ₂ in which the carbon is bonded to something mildly electronegative and the two doublets centered at

6.9 strongly suggest a 1,4-disubstituted aromatic compound.

3-bromomethyltoluene (3-bromomethyl-1-methylbenzene)

The proton NMR has three sets of peaks; a singlet at

4.3 (2H), a messy singlet around

7.1 (4H), and a singlet at

2.3 (3H). The singlet at

2.3 is consistent with an isolated CH₃ adjacent to a mildly electronegative center. The singlet at 4.3 is consistent with a CH₂ group adjacent to two mildly electronegative centers (X-CH₂-Y), and the singlet at

7.1 is consistent with a disubstituted aromatic compound. The substitution pattern is not what is normally seen in 1,4-disubstitution (two doublets), suggesting 1,2 or 1,3-disubstitution.

THANKS AND REGARD’S
DR ANTHONY MELVIN CRASTO Ph.D

amcrasto@gmail.com

MOBILE-+91 9323115463

GLENMARK SCIENTIST , INDIA
web link

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Diethyl benzylmalonate, IR, NMR, Mass

April 8, 2014 7:01 am / 1 Comment on Diethyl benzylmalonate, IR, NMR, Mass

structure

The mass spectrum displays a molecular ion, an m-45 and a peak at m/e = 91, all of which are consistent with a molecule containing benzyl and ethoxy groups.

The ¹³C spectrum contains six peaks, indicating that the molecule has some elements of symmetry. The quartet at 56 and the triplet at 71 represent a CH₃ and a CH₂ group which are deshielded by electronegative atoms (most likely oxygen); the peaks at 161 – 128 are in the aromatic region; the fact that three doublets and one singlet are observed strongly suggests monosubstitution.

The proton NMR also shows evidence for two ethyl groups, a CH-CH₂– group, and a monosubstituted aromatic group; the chemical shift suggests that the carbons of the CH-CH₂– adjacent to one or more electronegative groups.

The IR is consistent with an aromatic compound containing a carbonyl group.

The simplest structure which is consistent with all of these data would be an aromatic compound linked via a -CH₂CH group to a diethyl ester.

Structure:

IUPAC Name: ethyl ethyl benzylpropanedioate (diethyl benzylmalonate)

607-81-8

C₁₄H₁₈O₄; MW = 250.29

1H NMR

The proton NMR has a coupled quartet and a triplet, consistent with an ethyl group in which the CH₂ (at 4.1) is adjacent to an electronegative atom (most likely oxygen). The presence of a coupled triplet and doublet suggests the presence of a CH-CH₂– group in which both carbons are adjacent to one or more electronegative atoms. The singlet at 7.1 is consistent with a monosubstituted aromatic compound.

NMR Spectrum

13C NMR

The ¹³C spectrum contains nine peaks, indicating that the molecule has some elements of symmetry. The quartet at 14 and the triplet at 60 represent a simple CH₃ and a CH₂ which is deshielded by an electronegative atom (most likely oxygen); the doublet at 58 and the triplet at 36 are CH and CH₂ groups which are adjacent to one or more electronegative groups. The peaks at 141 – 125 are in the aromatic region; the fact that three doublets and one singlet are observed strongly suggests monosubstitution.

¹³C NMR Assignments: C-13 assignments

MASS

The mass spectrum consists of a molecular ion at 250, a base peak at 91 (a benzyl group), an m-45 peak at 205, indicating the presence of an ethoxy group; other significant peaks at 131 and 176 must be consistent with the proposed structure. The spectrum is consistent with a molecule containing ethoxy and benzyl groups.

Mass Spectrum

Mass Spectrum Fragments: C-13 assignments

3400-3200 cm^–¹: no OH peak 3100 cm^–¹: small peak, suggesting unsaturated CH 2900 cm^–¹: strong peak suggesting saturated CH 2200 cm^–¹: no unsymmetrical triple bonds 1730 cm^–¹: strong carbonyl 1610 and 1500 cm^–¹: weak peaks, vaguely consistent with aromatic carbon-carbon double bonds

ADDITIONAL INFO FOR READER ON SPECTROSCOPY

SEE THE FUN WHEN A CARBONYL IS INTRODUCED

BENZOYLMALONIC ACID DIETHYL ESTER Structure

1H NMR

13 C NMR

MASS

RAMAN

4-methoxyphenyl methanol, (4-メトキシフェニル)メタノール NMR, IR , MASS

April 8, 2014 6:19 am / 3 Comments on 4-methoxyphenyl methanol, (4-メトキシフェニル)メタノール NMR, IR , MASS

(4-methoxyphenyl)methanol

Structure:

IUPAC Name: 4-methoxyphenyl methanol

C₆H₁₀O₃; MW = 138.17

The molecule contains two oxygens, and from the analysis, contains four double bonds, carbonyls or rings. The large number of degrees of unsaturation strongly suggests an aromatic compound (DU = 4).

The mass spectrum displays a molecular ion, which is the base peak, an m-1 and an m-17, all of which are consistent with a simple alcohol.

The ¹³C spectrum contains six peaks, indicating that the molecule has some elements of symmetry. The quartet at 56 and the triplet at 71 represent a CH₃ and a CH₂ group which are deshielded by electronegative atoms (most likely oxygen); the peaks at 161 – 128 are in the aromatic region; the fact that two doublets and two singlets are observed strongly suggests 1,4-disubstitution.

The proton NMR also shows evidence for aromatic 1,4-disubstitution and suggests that the methyl and methylene are isolated and adjacent to electronegative groups. A peak consistent with an alcoholic OH can also be seen.

The IR is consistent with an aromatic alcohol containing no carbonyl group, suggesting that the second oxygen is involved in an ether linkage.

The simplest structure which is consistent with all of these data would be an aromatic compound containing an alcohol group and a methyl ether, situated 1,4 relative to each other.

IH NMR

The proton NMR has two doublets at 6.9, consistent with aromatic 1,4-disubstitution, and three singlets, areas 3, 2 and 1. The singlets at 3.6 and 4.7 are highly shifted and suggest isolated CH₃ and CH₂ groups adjacent to one or more electronegative atoms or groups. The singlet, area 1, would be consistent with an alcohol.

NMR Spectrum

Predict NMR spectrum

13C NMR

The ¹³C spectrum contains six peaks, indicating that the molecule has some elements of symmetry. The quartet at 56 and the triplet at 71 represent a CH₃ and a CH₂ group which are deshielded by electronegative atoms (most likely oxygen); the peaks at 161 – 128 are in the aromatic region; the fact that two doublets and two singlets are observed strongly suggests 1,4-disubstitution.

¹³C NMR Data: q-56.0; t-71.0; d-114.3; d-128.3; s-160.9; s-133.2

¹³C NMR Assignments: C-13 assignments

MASS

The mass spectrum consists of a molecular ion at 138, which is also the base peak, an m-1 peak at 137, indicating the presence of a labile hydrogen (OH or CHO), and an m-17 peak (loss of HO-). The spectrum is consistent with an alcohol which cannot readily break down to form other stable radical cations.

Mass Spectrum

Mass Spectrum Fragments: C-13 assignments

3400-3200 cm^–¹: strong OH peak 3100 cm^–¹: small peak, suggesting possible unsaturated CH 2900 cm^–¹: strong peak suggesting saturated CH 2200 cm^–¹: no unsymmetrical triple bonds 1710 cm^–¹: no carbonyl 1610 and 1500 cm^–¹: sharp peaks, consistent with aromatic carbon-carbon double bonds

Synthetic Communications, 18, p. 613, 1988 DOI: 10.1080/00397918808064019
Synthesis, p. 1081, 1984
Tetrahedron Letters, 32, p. 3243, 1991

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