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DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

How to Extend the Life of a Patent

 PATENTS  Comments Off on How to Extend the Life of a Patent
Dec 182016
 

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ALL CREDIT TO WIKIHOW

How to Extend the Life of a Patent

Three Methods:

Determining Eligibility

Extending Your Patent

Contacting Congress

A patent ensures that an inventor is able to profit from his or her invention by preventing others from making, using, selling, or importing it without consent. Once the patent expires, the invention is free for the public to use without paying you. If you meet certain requirements, you may wish to extend your patent.Take advantage of this opportunity to have extra time added to your patent term and keep your invention out of the public domain longer.

1

Determining EligibilityImage titled Get a Patent Step 3

  1. Determine the status of your patent. The United States Patent and Trademark Office (USPTO) keeps a website database of patent information. Access the USPTO database to check on your patent status. If you can’t find all the information you are looking for in the text-based display, then look at the patent image in PDF format.

    • You can also look up European patents here.
    • Or check Google Patents.
    • Patents cannot be renewed and you can’t get the rights to an expired patent. [1]
  2. Image titled Patent an Idea Step 7
    Know what kind of patent you have. In the US, 2 main types of patents are given: utility patents or design patents. Utility patents cover the function of an invention and design patents protect the way an invention looks. Utility patents generally last 20 years, while design patents last 14 years or 15 years for those filed on or after May 13, 2015. There are also 20 year long plant patents for inventors who asexually reproduce a newly discovered or invented variety of plant.[2]
  3. Image titled Do Research Step 14
    Find out if you qualify. Patent extensions are sometimes granted if there are government regulatory delays or if newer laws extend the length of a patent. Sometimes, with very strong justification, you can try to get Congress to pass a bill to extend your patent. If you fall into one of these categories, then you may be able to get your patent extended.
  4. Image titled Interrogate Someone Step 16
    Be aware that extensions may not be an option. For most inventions, the given term for your patent will stand. Recognize that you may not be able to extend your patent for this particular invention. Focus, instead, on developing a new invention that you can then get a new patent for.
 2
Extending Your Patent
  1. Image titled Calculate Profit Step 12
    Get a term adjustment. If you filed your patent after May 29, 2000 and your patent was delayed because the USPTO was taking longer than normal to process the paperwork, you may be eligible to file for an extension. The extension will cover the time lost from your patent term for the delay. The length of the extension you are approved for will depend on the delay time frame, but will not be longer than 5 years.
  2. Image titled Buy a Stock Without a Stockbroker Step 5
    Increase your original patent term. If you were initially granted less time than later legislation allows, you may be eligible to request an extension on your patent for the newer patent term. Under the Uruguay Rounds Agreements Act, utility patents granted before June of 1995 may be given an extension to 20 years instead of the original 17 years. This does not apply to design patents.
  3. Image titled Be a Successful Entrepreneur Step 2
    Get an extension under the Hatch-Waxman Act. A patent term restoration under the Hatch-Waxman Act is sometimes given to those who qualify.This applies to those whose products or processes, such as medications, medical devices, food and color additives, require testing and approval by the Food and Drug Administration’s (FDA) before they can be marketed. The period of time that you were unable to sell your product because you were awaiting FDA approval may be restored as an extension to the original patent. [3]
  4. Image titled Patent an Idea Step 11

    File for an extension with the United States Patent and Trademark Office (USPTO). All application forms for patent extensions can be found on the USPTO website: here for applications filed before September 16, 2012 and here for those filed after this time frame. Know that there are filing fees associated with this application.The process for filing for the extension depends upon which reason for extension the patent falls under.

    • Generally, the application for extension must be in writing, include the identifying information for the patent, information about why the applicant is entitled to an extension, relevant dates to determine the length of the extension, copies of the patent documents, etc.
    • Be sure to check with the USPTO for the exact amount of the fee (around $1,000) and the proper procedure for requesting the extension for your case.
  5. Image titled Delegate Step 11
    Wait to hear back from the USPTO. It can take up to several months for the USPTO to process your request. As with any government process, patience is best. If you are eligible and have a good reason for an extension, then there’s a chance you could be approved so waiting is worth it.
  6. Image titled Get a Patent Step 9

    Request an administrative hearing. If your extension request is denied, you have the right to appeal your denied request. Appeal forms can be found on the USPTO website: here for applications filed before September 16, 2012 and here for those filed after this time frame. Reasons for denial include defects in the paperwork you submitted to the USPTO asking for the extension and your invention being ineligible for extension. File an appeal and address any of the issues that your extension was denied in your written appeal.

    • The appeals process begins with your Notice of Appeal and fee payment. It will continue through various steps until it reaches the Patent Trial and Appeal Board. The board will make a decision on your case and complete the appeals process.
  7. Image titled Announce Your Retirement Step 3
    Meet with an intellectual property lawyer. It could be very beneficial to consult with an attorney to review your options, especially if your request is denied. Your lawyer may be able to offer suggestions and ways to supplement your application. Filing for a patent extension can be complex and your lawyer can ensure that it is done correctly.
 3

Contacting Congress

  1. Image titled Develop Critical Thinking Skills Step 18

    Be realistic. This is the least common form of attempting to extend a patent. Congress may not grant your request unless you have very convincing evidence for doing so. You also may need strong support from the community or a special interest group with persuasive lobbyists on your side.

    • Congress extended the copyright of works to 95 years over the original 75 in 1998. This was due mainly to influential corporations like the Walt Disney Company lobbying for the modification.[4] Keep the kind of influence you may require in mind when you decide to send a bill requesting a patent extension through Congress on your behalf.
  2. Image titled Get a Job Fast Step 1
    Find a representative. Do some research on representatives in your area or someone you think would want to sponsor you in extending your patent. You will need to convince him or her that there is a very important reason you must extend your patent. It is best if they have a record of supporting the type of invention you have or are connected in some way to that field.
    • Only a member of Congress can propose private legislation to the legislative body.
  3. Image titled Do Research Step 10
    Draft a bill. It’s a good idea to do as much of the legwork as possible before approaching your representative. Your bill should be written in legal language and go over the reasons your patent should be granted an extension. You can check existing bills on the Congress website to get an idea what a bill looks like. It might be helpful to consult with a patent attorney when you’re writing this as legalese can be difficult to master.[5]
    • Create a preamble. This is an introduction and general overview about your patent, the date it will expire and an explanation of why you need an extension on your patent.
    • Write up a body clause. This is the meat of your biIl and contains clauses that show what action needs to be taken—in this case, you want your patent to be extended.
    • Finish with an enactment clause. This tells when you want the bill to take effect. This will be the day your patent is due to expire.
    • Know that bills which need to take effect in 90 days or less will need 2/3 majority vote, while those that take effect after that time period will only require a majority vote. Send your bill in as early as possible.[6]
  4. Image titled Write a Grant Proposal Step 22
    Submit your bill to your potential sponsor. Contact your representative by phone or email. Many have websites where you can fill out a form to submit your case. Be sure to ask what the process is like and when you can expect to hear back.
  5. Image titled Communicate Effectively Step 9
    Get a lobbyist to represent you. If your patent is important to certain groups or not extending it could cause harm, then look for someone with contacts to represent you. Lobbyist groups can put pressure on Congress to extend your patent. In order to do this, you need to have a good cause with far-reaching effects if your patent is not extended.
  6. Image titled Excel in a Retail Job Step 2
    Be patient. The legislative process can take time. It must go through multiple committees before the house will vote on it. After that, it must be signed in. The length of time this will take varies and is something you should discuss with your sponsor.
Tips
  • It is best to file for an extension as soon as possible, as the USPTO generally takes months to process most filings.
 Warnings
  • The request for patent extension should be made 3 months prior to the date on which the patent is set to expire.

Sources and Citations

  1. ↑ http://www.bpmlegal.com/patqa.html#2
  2. ↑ http://www.uspto.gov/patents-getting-started/patent-basics/types-patent-applications/general-information-about-35-usc-161
  3. ↑ http://corporate.findlaw.com/intellectual-property/patent-term-extensions-and-restoration-under-the-hatch-waxman-act.html#sthash.xuVfZJXF.dpuf
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Selection and justification of starting materials: new Questions and Answers to ICH Q11 published

 regulatory  Comments Off on Selection and justification of starting materials: new Questions and Answers to ICH Q11 published
Dec 082016
 

 

The ICH Q11 Guideline describing approaches to developing and understanding the manufacturing process of drug substances was finalised in May 2012. Since then the pharmaceutical industry and the drug substance manufacturers had time to get familiar with the principles outlined in this guideline. However, experience has shown that there is some need for clarification. Thus the Q11 Implementation Working Group recently issued a Questions and Answers Document.

http://www.gmp-compliance.org/enews_05688_Selection-and-justification-of-starting-materials-new-Questions-and-Answers-to-ICH-Q11-published_15619,15868,S-WKS_n.html

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The ICH Q11 Guideline describes approaches to developing and understanding the manufacturing process of drug substances. It was finalised in May 2012 and since then the pharmaceutical industry and the drug substance manufacturers had time to get familiar with the principles outlined in this guideline. However, experiences during implementation of these principles within this 4 years period have shown that there is need for clarification in particular with regard to the selection and justification of starting materials.

On 30 November 2016 the ICH published a Questions and Answers document “Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities)” which was developed by the Q11 Implementation Working Group. This document aims at addressing the most important ambiguities with respect to starting materials and at promoting a harmonised approach for their selection and justification as well as the information that should be provided in marketing authorisation applications and/or Drug Master Files.

In the following some examples of questions and answers from this document:

Question:
ICH Q11 states that “A starting material is incorporated as a significant structural fragment into the structure of the drug substance.” Why then are intermediates used late in the synthesis, which clearly contain significant structural fragments, often not acceptable as starting materials?

Answer:
The selection principle about “significant structural fragment” has frequently been misinterpreted as meaning that the proposed starting material should be structurally similar to the drug substance. However, as stated in ICH Q11, the principle is intended to help distinguish between reagents, catalysts, solvents, or other raw materials (which do not contribute a “significant structural fragment” to the molecular structure of the drug substance) from materials that do. … The presence of a “significant structural fragment” should not be the sole basis for of starting material selection. Starting materials justified solely on the basis that they are a “significant structural fragment” probably will not be accepted as starting materials by regulatory authorities, as the other principles for the appropriate selection of a proposed starting material also require consideration.

Question:
Do the ICH Q11 general principles for selection of starting materials apply to processes where multiple chemical transformations are run without isolation of intermediates?

Answer:
Yes. The ICH Q11 general principles apply to processes where multiple chemical transformations are run without isolation of intermediates. In the absence of such isolations (e.g., crystallization, precipitations), other unit operations (e.g., extraction, distillation, the use of scavenging agents) should be in place to adequately control impurities and be described in the application. The drug substance synthetic process should include appropriate unit operations that purge impurities.
The ICH Q11 general principles also apply for sequential chemical transformations run continuously. Non isolated intermediates are generally not considered appropriate starting materials.

Question:
Is a “starting material” as described in ICH Q11 the same as an “API starting material” as described in ICH Q7?

Answer:
Yes. ICH Q11 states that the Good Manufacturing Practice (GMP) provisions described in ICH Q7 apply to each branch of the drug substance manufacturing process beginning with the first use of a “starting material”. ICH Q7 states that appropriate GMP (as defined in that guidance) should be applied to the manufacturing steps immediately after “API starting materials” are entered into the process … . Because ICH Q11 sets the applicability of ICH Q7 as beginning with the “starting material”, and ICH Q7 sets the applicability of ICH Q7 as beginning with the “API starting material”, these two terms are intended to refer to the same material.
ICH Q7 states that an “API Starting Material” is a raw material, intermediate, or an API that is used in the production of an API. ICH Q7 provides guidance regarding good manufacturing practices for the drug substance; however, it does not provide specific guidance on the selection and justification of starting materials. When a chemical, including one that is also a drug substance, is proposed to be a starting material, all ICH Q11 general principles still need to be considered.

With the recent publication of this draft Q&A Document with the complete title “Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities) Questions and Answers (regarding the selection and justification of starting materials)” on the ICH website it reached Step 2b of the ICH Process and now enters the consultation period.  Comments may be provided by e-mailing to the ICH Secretariat at admin@ich.org.

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extra info…………
A PRESENTATION

 

 

 

QbD Takes a Step Forward with ICH Q11

Ever since the FDA issued its landmark guidance Pharmaceutical GMPs-A Risk Based Approach in 2004, the industry has been struggling with how to demonstrate process understanding as a basis for quality. Bolstered by guidance from ICH, specifically Q6-Q10, the pieces have long been in place to build a solution that is philosophically consistent with these best practice principles. Even so, the evolution to process understanding as a basis for quality has been slow. Pressure to accelerate this transformation spiked in 2011 when the FDA issued its new guidance on process validation that basically mandated the core components of ICH Q6-10 as part of Stages 1 and 2. To be fair, enforcement has been uneven and that fact has further impeded adoption, with the compliance inspectors themselves struggling to acquire the necessary skills to fully evaluate statistical arguments of process control and predictability.

One area debated since 2008 is the application of GMPs and demonstration of control for drug substances. Drug substance suppliers and drug product manufacturers have used the tenets of ICH Q7A as the foundation for deciding where GMPs can be reasonably implemented, to establish the final intermediate (FI) and the regulatory starting material (RSM). However, the ability to support the quality of the drug substance has a profound impact on the ability to defend the drug product quality. In the last few years it has become apparent that it was not reasonable to apply the same requirements for drug products to drug substances because the processes can be markedly different. In response to this need, the ICH issued a new guidance; Q11: Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities). The key ICH documents that impact Q11 are shown in Figure 1.


Figure 1. Guidances Impacting ICH Q11.

The FDA formally adopted ICHQ11 in November 2012 and its purpose is two-fold. First, it offers guidance on the information to provide in Module 3 of the Common Technical Document (CTD) Sections 3.2.S.2.2 – 3.2.S.2.6 (ICH M4Q). Second, and perhaps most importantly, it attempts to clarify the concepts defined in the ICH guidelines on Pharmaceutical Development (Q8), Quality Risk Management (Q9), and Pharmaceutical Quality System (Q10) as they pertain to the development and manufacture of drug substances.

What makes ICH Q11 so important is its emphasis on control strategy. This concept was introduced in ICH Q10 as “a planned set of controls, derived from current product and process understanding that assures process performance and product quality.”

Within the drug product world, the control strategy concept has been elusive as industry grapples with moving from a sample-and-test concept of quality to one of process understanding and behavior. This concept is even more removed for drug substance manufacturers and, in some cases, is more difficult to implement. But Q11 is much more than a mere framework for control strategy. The guidance is structured very similarly to the concepts discussed in the new 2011 Process Validation guidance. Looking closely, Q11 addresses:
• Product Design/Risk Assessment/CQA Determination
• Defining the Design Space and establishing a control strategy
• Process validation and analysis
• Information required for Sections 3.2.S.2.2 – 3.2.S.2.6 of the eCTD
• Lifecycle management

Product design/Risk assessment/CQA determination

Within the context of process development, the guidance defines similar considerations to those defined in the Stage 1 activity of Process Validation. Understanding the quality linkage between the drug substance’s physical, chemical, and microbiological characteristics, and the final drug products’ Quality Target Product Profile (QTPP), is the primary objective of the product and process design phase. The product’s QTPP is comprised of the final product Critical to Quality Attributes (CQAs). Identifying the raw material characteristics of the drug substance that can impact the drug product is a critical first step in developing a defensible control strategy. Employing risk analysis tools at the outset can help focus the process development activities upon the unit operations that have the potential to impact the final product’s CQAs. In the case of biological drug substances, any knowledge regarding mechanism of action and biological characterization, such as studies that evaluate structure-function relationships, can contribute to the assessment of risk for some product attributes.

Drug substance CQAs typically include those properties or characteristics that affect identity, purity, biological activity, and stability of the final drug product. In the case of biotechnological/biological products, most of the CQAs of the drug product are associated with the drug substance and thus are a direct result of the design of the drug substance or its manufacturing process. When considering CQAs for the drug substance, it is important to not overlook the impact of impurities because of their potential impact on drug product safety. For chemical entities, these include organic impurities (including potentially mutagenic impurities), inorganic impurities such as metal residues, and residual solvents.

For biotechnological/biological products, impurities may be process-related or product-related (see ICH Q6B). Process-related impurities include: cell substrate-derived impurities (e.g., Host Cell Proteins [HCP] and DNA); cell culture-derived impurities (e.g., media components); and downstream-derived impurities (e.g., column leachable). Determining CQAs for biotechnology/biological products should also include consideration of contaminants, as defined in Q6B, including all adventitiously introduced materials not intended to be part of the manufacturing process (e.g., viral, bacterial, or mycoplasma contamination).

Defining the design space and establishing a control strategy

ICH Q8 describes a tiered approach to establishing final processing conditions that consists of moving from the knowledge space to the process design space and finally the control space. ICH Q8 and Q11 define the Design Space as “the multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality.” In the drug product world the terminology typically applied to the design space is the Proven Acceptable Range (PAR) that used to equate to the validated range.

Here is why this is important: the ability to accurately assess the significance and effect of the variability of material attributes and process parameters on drug substance CQAs, and hence the limits of a design space, depends on the extent of process and product understanding. The challenge with drug substance processes is where to apply the characterization. ICH Q7A recognizes that upstream of the RSM does not require GMP control. The design space can be developed based on a combination of prior knowledge, first principles, and/or empirical understanding of the process. A design space might be determined per unit operation (e.g., reaction, crystallization, distillation, purification), or a combination of selected unit operations should generally be selected based on their impact on CQAs.

In developing a control strategy, both upstream and downstream factors should be considered. Starting material characteristics, in-process testing, and critical process parameters variation control are the key elements in a defensible control strategy. For in-process and release testing criteria the resolution of the measurement tool should be considered before making any conclusions.

Process validation

ICH Q11’s description of process validation mimics the same description in ICH Q7A but offers up an alternative for continuous verification that mirrors the concepts in ICH Q8 and the new process validation guidance. As mentioned, the enforcement of the new guidance by the FDA has been uneven, but positioning the process validation to satisfy the new guidance requires the drug substance manufacturer to formally implement characterization and validation standards, just as a drug product manufacturer would be required to do.

Life-cycle management

The quality system elements and management responsibilities described in ICH Q10 are intended to encourage the use of science-based and risk-based approaches at each lifecycle stage, thereby promoting continual improvement across the entire product lifecycle. There should be a systematic approach to managing knowledge related to both drug substance and its manufacturing process throughout the lifecycle. This knowledge management should include but not be limited to process development activities, technology transfer activities to internal sites and contract manufacturers, process validation studies over the lifecycle of the drug substance, and change management activities.

Conclusion

The new ICH Q11 guidance represents the most recent example of the FDA’s commitment to the principles of QbD to define an integrated framework for implementing the principles of ICH Q6-Q10. Although the guidance does not mandate adopting ICH Q8, the considerations required to create a defensible control strategy require a much higher level of process understanding than the conventional approach of sample and test, once the foundation of product development. Defining the requirements is another example of where the FDA is going in terms of expectations for drug substance and drug product understanding. If effectively enforced, this can be a significant step forward, pushing the industry toward a QbD philosophy for process and product development.

/////////Selection, justification, starting materials,  ICH Q11 , ich, qbd

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Scientific Update, UK, Course on ‘Chemical Development & Scale Up in the Pharmaceutical Industry’, Sea Princess Hotel, Mumbai, India, 6– 8th Feb 2017

 CONFERENCE  Comments Off on Scientific Update, UK, Course on ‘Chemical Development & Scale Up in the Pharmaceutical Industry’, Sea Princess Hotel, Mumbai, India, 6– 8th Feb 2017
Dec 032016
 

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Scientific Update, UK,  Course on ‘Chemical Development & Scale Up in the Pharmaceutical Industry’, Sea Princess Hotel, Mumbai, India, 6th – 8th February 2017

Want to download Brochure click  View Brochure  6-8 FEB 2017

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A PRESENTATION BROCHURE

 

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6-8 FEB 2017

 

 

PLEASE SCROLL WITH MOUSE TO VIEW BROCHURE

Want to download Brochure click : View Brochure   6-8 FEB 2017

 

Scientific Update, UK,  Course on ‘Chemical Development & Scale Up in the Pharmaceutical Industry’, Sea Princess Hotel, Mumbai, India, 6th – 8th February 2017……..Chemical process development is generally not taught as part of degree courses in higher education; the conversion of a synthetic route used for making milligram or gram quantities of a chemical into a process for manufacturing multi-kilogram and tonne quantities is typically learnt “on the job” by chemists in industry. For many years, little chemical development work was published in the literature, until the establishment of the Organic Process R & D journal by Dr Trevor Laird (Founder of Scientific Update). Even now, “tricks of the trade” are handed down within individual company organisations, and it can be difficult to gain an awareness of what is involved in chemical development, and of the skills and techniques required to efficiently scale up chemical processes.

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This three-day course, written and presented by highly experienced process chemists from the pharmaceutical and fine chemical industry, provides a comprehensive overview of this fascinating and important element of the chemical industry. A logical investigative approach to all aspects of chemical development is described, with an abundance of case studies from literature, conferences and private communications. The multi-disciplinary nature of chemical development is emphasised, from the initial interaction with laboratory research scientists to the vital partnership with chemical engineers in the pilot plant and in the production environment. The lectures are interspersed with interactive problem sessions, enabling participants to share in the problem solving and troubleshooting typically experienced during chemical development.

Want to download Brochure click  View Brochure     6-8 FEB 2017

TRAINING COURSES

EVENT

Title:Chemical Development & Scale-Up in the Fine Chemical & Pharmaceutical Industries

Subtitle:Principles and Practice

When:06.02.2017 – 08.02.2017

Tutors:

John Knight

Will Watson

Where:The Sea Princess Hotel – MumbaiBrochure  View Brochure  6-8 FEB 2017

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THE SEA PRINCESS HOTEL

DESCRIPTION

AT THE END OF THE COURSE PARTICIPANTS WILL HAVE GAINED:

  • A logical investigative approach to chemical development and optimisation.
  • An insight into the factors involved in development and scale-up.
  • An appreciation of chemical engineering concepts, particularly mixing, heat transfer and process control.
  • A preliminary knowledge of statistical methods of optimisation.
  • Improved ability to decide which parts of the chemical process to examine in detail
  • Ideas for efficient resource allocation
  • Improved troubleshooting and problem solving ability

Kind regards,

Claire Francis

Dr Claire Francis

Director

Scientific Update Ltd, Maycroft Place

Stone Cross, Mayfield, East Sussex

TN20 6EW, UK

T: +44 (0) 1435 873062

E: claire@scientificupdate.co.uk

W: www.scientificupdate.co.uk

Want to download Brochure click :View Brochure  6-8 FEB 2017

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//////////course, scientific update, sea princess, mumbai, india, claire francis, will watson, helen, john knight, Chemical Development , Scale, Pharmaceutical Industry, uk, feb

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An Efficient Synthesis of 1-(2-Methoxyphenoxy)-2,3-epoxypropane: Key Intermediate of β-Adrenoblockers

 spectroscopy, SYNTHESIS  Comments Off on An Efficient Synthesis of 1-(2-Methoxyphenoxy)-2,3-epoxypropane: Key Intermediate of β-Adrenoblockers
Nov 302016
 

Abstract Image

An efficient process for the preparation of 1-(2-methoxyphenoxy)-2,3-epoxypropane, a key intermediate for the synthesis of ranolazine is described.

http://pubs.acs.org/doi/suppl/10.1021/op300056k

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Preparation of 1-(2-Methoxyphenoxy)-2,3-epoxypropane 4.

To a stirring solution of 2-methoxy phenol 2 (10 kg, 80.55 mol) and water (40 L) at about 30 °C was added sodium hydroxide (1.61 kg, 40.25 mol) and water (10 L). After stirring for 30−45 min, epichlorohydrin 3 (22.35 kg, 241.62 mol) was added and stirred for 10−12 h at 25−35 °C. Layers were separated, and water (40 L) was added to the organic layer (bottom layer) containing product. Sodium hydroxide solution (3.22 kg, 80.5 mol) and water (10 L) were added at 27 °C and stirred for 5−6 h at 27 °C.

The bottom product layer was separated and washed with sodium hydroxide solution (3.0 kg 75 mol) and water (30 L). Excess epichlorohydrin (3) was recovered by distillation of the product layer at below 90 °C under vacuum (650−700 mmHg) to give 13.65 kg (94%) of title compound with 98.3% purity by HPLC, 0.2% of 2- methoxy phenol 2, 0.1% of epichlorohydrin 3, 0.1% of chlorohydrin 11, 0.3% of dimer 12 and 0.3% of dihydroxy 13.

1 H NMR (400 MHz, CDCl3, δ) 6.8−7.0 (m, 4H), 4.3 (dd, J = 5.6 Hz, 5.4 Hz, 1H), 3.8 (dd, J = 5.6 Hz, 5.3 Hz, 1H), 3.7 (s, 3H), 3.2−3.4 (m, 1H), 2.8 (dd, J = 5.6 Hz, 5.4 Hz, 1H), 2.7 (dd, J = 5.6 Hz, 5.3 Hz, 1H);


IR (KBr, cm−1 ) 2935 (C−H, aliphatic), 1594 and 1509 (CC, aromatic), 1258 and 1231 (C−O−C, aralkyl ether), 1125 and 1025 (C−O−C, epoxide);


MS (m/z) 181 (M+ + H).



Compound Details

Properties
MWt 180.2
MF C10H12O3


CAS 2210-74-4

Glycidyl 2-methoxyphenyl ether
Guaiacol glycidyl ether

1H NMR PREDICT

13C NMR PREDICT

COSY PREDICT

logo

CREDIT……….http://www.molbase.com/en/synthesis_2210-74-4-moldata-95563.html

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RakeshwarBandichhor

DR REDDYS LABORATORIES

An Efficient Synthesis of 1-(2-Methoxyphenoxy)-2,3-epoxypropane: Key Intermediate of β-Adrenoblockers

† Innovation Plaza, IPD, R&D, Dr. Reddy’s Laboratories Ltd., Survey Nos. 42, 45,46, and 54, Bachupally, Qutubullapur – 500073, Andhra Pradesh, India

‡ Institute of Science and Technology, Center for Environmental Science, JNT University, Kukatpally, Hyderabad – 500 072, Andhra Pradesh, India

Org. Process Res. Dev., 2012, 16 (10), pp 1660–1664

DOI: 10.1021/op300056k

Publication Date (Web): September 14, 2012

Copyright © 2012 American Chemical Society

*Telephone: +91 4044346000. Fax: +91 4044346285. E-mail: rakeshwarb@drreddys.com.

////////////////1-(2-Methoxyphenoxy)-2,3-epoxypropane,  β-Adrenoblockers, ranolazine


COc2ccccc2OCC1CO1



OTHER COMPD

Glycidyl 2-methylphenyl ether technical grade, 90%


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Enantioselective Borohydride Reduction of Ketones Catalyzed by Optically Active Cobalt Complexes

 FLOW CHEMISTRY, flow synthesis  Comments Off on Enantioselective Borohydride Reduction of Ketones Catalyzed by Optically Active Cobalt Complexes
Nov 282016
 

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Homogeneous Enantioselective Catalysis in a Continuous-Flow Microreactor: Highly Enantioselective Borohydride Reduction of Ketones Catalyzed by Optically Active Cobalt Complexes

† Department of Chemistry, Keio University, Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan
‡ Hitachi Research Laboratory, Hitachi, Ltd., 832-2 Horiguchi, Hitachinaka, Ibaraki 312-0034, Japan
§ Hitachi Plant Technologies, Ltd., 603 Kandatsu-machi, Tsuchiura, Ibaraki 300-0013, Japan
Org. Process Res. Dev., 2012, 16 (6), pp 1235–1240
DOI: 10.1021/op300061k

Abstract

Abstract Image

Highly enantioselective homogeneous catalysis under continuous-flow conditions was established for the cobalt-catalyzed borohydride reduction of tetralone derivatives. A microreactor allowed higher reaction temperature with the residence time of 12 min than the corresponding batch system to maintain enantioselectivity as well as reactivity. The present system was directly applied to gram-scale synthesis to afford the reduced product with 92% ee.

////////////Homogeneous Enantioselective Catalysis,  Continuous-Flow Microreactor, Highly Enantioselective Borohydride, Reduction of Ketones Catalyzed,  Optically Active Cobalt Complexes

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Continuous-Flow Diazotization

 FLOW CHEMISTRY, flow synthesis  Comments Off on Continuous-Flow Diazotization
Nov 242016
 

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Figure

Characterization Data of Compound 7

Mp: 118–120 °C. MS (M + H+): 314.
HRMS (ESI) m/z: Calcd for C16H15N3NaO4, (M + Na+): 336.0960. Found: 336.0899.
IR (KBr) ν/cm–1: 3447, 3339, 1717, 1714, 1699, 1594.
1H NMR (CDCl3, 400 MHz) δ/ppm: 8.50 (s, 1H, Ar–H), 7.88 (d, J = 8.8 Hz, 1H, Ar–H), 7.76 (d, J = 7.6 Hz, 1H, Ar–H), 7.60 (d, J = 8.0 Hz, 1H, Ar–H), 7.54 (t, J = 7.2 Hz, 1H, Ar–H), 7.41 (t, J = 7.2 Hz, 1H, Ar–H), 6.71 (d, J = 9.2 Hz, 1H, Ar–H), 6.28 (br s, 2H, −NH2), 3.91 (s, 3H, −CH3), 3.89 (s, 3H, −CH3).
13C NMR (CDCl3, 100 MHz) δ/ppm: 168.2, 168.0, 152.9, 151.6, 143.4, 131.7, 131.2, 129.4, 128.8, 128.0, 126.3, 118.9, 117.1, 109.8, 52.3, 51.9.

 

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Continuous-Flow Diazotization for Efficient Synthesis of Methyl 2-(Chlorosulfonyl)benzoate: An Example of Inhibiting Parallel Side Reactions

† National Engineering Research Center for Process Development of Active Pharmaceutical Ingredients, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, P. R. China
‡ Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, P. R. China
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.6b00238
Publication Date (Web): November 17, 2016
Copyright © 2016 American Chemical Society
*Tel.: (+86)57188320899. E-mail: pharmlab@zjut.edu.cn.

Abstract

Abstract Image

An expeditious process for the highly efficient synthesis of methyl 2-(chlorosulfonyl)benzoate was described, which involved the continuous-flow diazotization of methyl 2-aminobenzoate in a three-inlet flow reactor via a cross joint followed by chlorosulfonylation in the tandem tank reactor. The side reaction such as hydrolysis was decreased eminently from this continuous-flow process even at a high concentration of hydrochloric acid. The mass flow rate of methyl 2-aminobenzoate was 4.58 kg/h, corresponding to an 18.45 kg/h throughput of diazonium salt solution. The potential of inhibiting parallel side reactions by conducting in a flow reactor was successfully demonstrated in this method.

//////////////chlorosulfonylation, continuous-flow,  diazotization,  parallel side reaction

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Generics: FDA´s New Guidance on Prior Approval Supplements

 regulatory  Comments Off on Generics: FDA´s New Guidance on Prior Approval Supplements
Nov 242016
 

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Generics: The US Food and Drug Administration (FDA) recently published a new Guidance regarding Prior Approval Supplements (PAS). Read more about FDA´s Guidance for Industry “ANDA Submissions – Prior Approval Supplements Under GDUFA“.

http://www.gmp-compliance.org/enews_05634_Generics-FDA%B4s-New-Guidance-on-Prior-Approval-Supplements_15721,Z-RAM_n.html

On October 14, 2016, the US Food and Drug Administration (FDA) published a new Guidance regarding Prior Approval Supplements (PAS).
FDA says that “this guidance is intended to assist applicants preparing to submit to FDA prior approval supplements (PASs) and amendments to PASs for abbreviated new drug applications (ANDAs)”.

Specifically, the guidance describes how the Generic Drug User Fee Amendments of 2012 (GDUFA) performance metric goals apply to:

  • A PAS subject to the refuse-to-receive (RTR) standards;
  • A PAS that requires an inspection;
  • A PAS for which an inspection is not required;
  • An amendment to a PAS;
  • Other PAS-related matters.

GDUFA is designed to speed the delivery of safe and effective generic drugs to the public and reduce costs to industry. That requires that FDA and human generic drug manufacturers meet certain requirements and commitments. “FDA committed to review and act on a certain percentage of PASs within a specified period from the date of submission for receipts in fiscal year (FY) 2015 through FY 2017. The percentage of PASs that FDA has committed to review and act on increases with each fiscal year; the deadlines for review also depend on whether consideration of a PAS requires an inspection.”

Changes to an approved application:
The criteria laid down in FDA regulations for submitting information as a PAS (major change), as a Changes Being Effected-Supplement (CBE-supplement, moderate change), or in an annual report (minor change) were not changed by GDUFA.

Timelines depending on inspections for PAS submissions:
The GDUFA goal date for a PAS depends on whether the PAS requires an inspection. If a PAS does not require an inspection, the goal date is 6 months from the date of submission; but if a PAS requires an inspection, the goal date is 10 months from the date of submission. An initial goal date of 6 months occasionally may change to a 10-month goal date if, during the review, FDA determines an inspection is necessary. If an amendment is made to a PAS, the GDUFA goal date associated with that PAS may be revised. FDA strongly recommends that, at the time of submission, a supplement should be complete and ready for a comprehensive review.

Submission of Supplements:
The following information should be provided on the first page of the PAS:

  • A statement indicating whether the PAS is for a new-strength product;
  • A statement indicating whether the submission is an amendment to a PAS, and if so the corresponding tier classification;
  • A statement indicating whether the PAS contains any manufacturing or facilities changes;
  • A list of the specific review disciplines to review the PAS (Chemistry, Labeling, DMF, Bioequivalence, Microbiology, or Clinical);
  • If expedited review is requested, the label Expedited Review Request should be placed prominently at the top of the submission. The submission should include a basis for the expedited review request.

It is possible to submit multiple PASs for the same chenge as “grouped supplements”. These are submitted to ANDAs by a single applicant for the same chemistry, manufacturing, and controls (CMC) change to each application. Because the grouped supplements are being reviewed together, generally they will have the same GDUFA goal date. Although the submissions are considered a group, each supplement in the group is considered its own individual submission and therefore would require a GDUFA PAS fee for each ANDA identified in the group.

Alternative Submissions:

  • Identify a lead ANDA for a group of PASs (only one fee is paid, or fewer than all the fees for the group are paid);
  • For some changes (e.g., widening of an approved specification or introduction of a new API supplier) once a PAS is submitted and approved, subsequent supplements for the same change to other ANDAs may be classified as CBE-30s;
  • A comparability protocol submitted in a PAS to an ANDA for a specific drug product, once approved, may justify a reduced reporting category for the same change in subsequent supplements to that ANDA.

If FDA finds that a supplement submitted as a CBE supplement should have been submitted as a PAS, it will notify the applicant. The applicant is not required to withdraw the CBE supplement because when FDA sends a letter explaining that the applicant’s submission is not accepted as a CBE supplement, FDA administratively closes the CBE supplement, and it is considered withdrawn. The applicant may resubmit the supplement as a PAS for FDA approval before distribution of the drug product, along with the required GDUFA user fee. The GDUFA performance metric goals and applicable user fees will apply to that PAS and the GDUFA review clock will start from the date of submission of that PAS.

For more information please see the FDA Guidance for industry “ANDA Submissions – Prior Approval Supplements Under GDUFA“.

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///////////Generics, FDA,  New Guidance,  Prior Approval Supplements

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WO 2016181414, IVACAFTOR, NEW PATENT, COUNCIL OF SCIENTIFIC & INDUSTRIAL RESEARCH

 PATENTS  Comments Off on WO 2016181414, IVACAFTOR, NEW PATENT, COUNCIL OF SCIENTIFIC & INDUSTRIAL RESEARCH
Nov 242016
 

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CSIR, Dr. D. Srinivasa Reddy

WO2016181414, PROCESS FOR THE SYNTHESIS OF IVACAFTOR AND RELATED COMPOUNDS

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016181414&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

REDDY, Dumbala Srinivasa; (IN).
NATARAJAN, Vasudevan; (IN).
JACHAK, Gorakhnath Rajaram; (IN)

COUNCIL OF SCIENTIFIC & INDUSTRIAL RESEARCH [IN/IN]; Anusandhan Bhawan, Rafi Marg New Delhi 110001 (IN)

The present patent discloses a novel one pot two-step process for the synthesis of ivacaftor and related compounds of [Formula (I)], wherein R1, R2, R3, R4, R5, R6, R7 and Ar1are as described above; its tautomers or pharmaceutically acceptable salts thereof starting from indole acetic acid amides

See Eur J Org Chem, Nov 2015, for an article by the inventors, describing a process for preparing ivacaftor using 4-quinolone-3-carboxylic acid amides. The inventors appear to be based at National Chemical Laboratories of CSIR.

Ivacaftor, also known as N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l,4-dihydro-4-oxoquinoline-3-carboxamide, having the following Formula (A):

Formula (A)

[003] Ivacaftor was approved by FDA and marketed by vertex pharma for the treatment of cystic fibrosis under the brand name KALYDECO® in the form of 150 mg oral tablets. Kalydeco® is indicated for the treatment of cystic fibrosis in patients age 6 years and older who have a G55ID mutation in the CFTR (cystic fibrosis transmembrane conductance regulator)gene.

[004] U.S. 20100267768 discloses a process for preparation of ivacaftor, which involves the coupling of 4-oxo-l,4-dihydro-3- quinoline carboxylic acid with hydroxyl protected phenol intermediate in the presence of propyl phosphonic anhydride (T3P®) followed by deprotection of hydroxyl protection group and optional crystallization with isopropyl acetate. The publication also discloses the use of highly expensive coupling reagent, propyl phosphonic anhydride; which in turn results to an increase in the manufacturing cost. The process disclosed is schematically represented as follows:

[005] Article titled “Discovery of N-(2,4-Di-te -butyl-5-hydroxyphenyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide (VX-770, Ivacaftor), a Potent and Orally Bioavailable CFTR Potentiator” byHadida,S et. al in . Med. Chem., 2014, 57 (23), pp 9776-9795 reportsN-(2,4-di-teri-butyl-5-hydroxyphenyl)-4-oxo- 1 ,4-dihydroquinoline-3-carboxamide (VX-770, 48, ivacaftor), an investigational drug candidate approved by the FDA for the treatment of CF patients 6 years of age and older carrying the G551D mutation.

[006] WO 2014125506 A2 discloses a process for the preparation of ivacaftor in high yield and purity by using novel protected quinolone carboxylic acid compounds as intermediates.

[007] Article titled “Expeditious synthesis of ivacaftor” by Jingshan Shen et. al in Heterocycles, 2014, 89 (4), pp 1035 – 1040 reports an expeditious synthesis for ivacaftor featuring modified Leimgruber-Batcho procedure. The overall yield is 39% over six steps from commercially available 2-nitrobenzoyl chloride.

[008] U.S.2011/064811 discloses a process for preparation of ivacaftor, which involves condensation of 4-oxo-l,4-dihydro-3- quinolone carboxylic acid with 5- amino-2,4-di-(tert-butyl)phenol in the presence of HBTU followed by the formation of ethanol crystalate, which is then treated with diethyl ether to yield ivacaftor as a solid.

[010] U.S. 7,495,103 discloses modulators of ATP-binding cassette transporters such as ivacaftor and a process for the preparation of modulators of ATP-binding cassette transporters such as quinolone compounds. The process includes condensation of 4-oxo-l,4-dihydro-3 -quinolone carboxylic acid with aniline in presence of 2-(lH-7-azabenzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluoro phosphate methanaminium (HATU) as shown:

[011] U.S. 2011/230519 discloses a process for preparation of 4-oxo-l,4-dihydro-3-quinoline carboxylic acid by reaction of aniline with diethylethoxymethylenemalonate at 100-110°C followed by cyclization in phenyl ether at temperature 228-232°C and then hydrolysis, as shown below:

[012] US 7,402,674 B2 discloses 7-Phenylamino-4-quinolone-3-carboxylic acid derivatives, process for their preparation and their use as medicaments.

[013] US 4,981,854 discloses l-aryl-4-quinolone-3 carboxylic acids, processes for their preparation and anti-bacterial agents and feed additives containing these compounds.

Article titled “Ozonolysis Applications in Drug Synthesis” by Van Ornum,S.G. ; Champeau,R.M.; Pariza,R. in Chem. Rev., 2006, 106 (7), pp 2990-3001 reports that ozonolysis for the synthesis of numerous interesting bioactive natural products and pharmaceutical agents.

[014] Article titled “Safe Execution of a Large-Scale Ozonolysis: Preparation of the Bisulfite Adduct of 2-Hydroxyindan-2-carbox-aldehyde and Its Utility in a Reductive Animation” by RaganJ.A. et. al. in Org. Proc. Res. Dev., 2003, 7 (2), pp 155-160 reports various routes to bisulfite adduct, the most efficient of which involved vinyl Grignard addition to 2-indanone followed by ozonolysis and workup with aqueous NaHS03 to effect reduction and bisulfite formation in a single pot. The utility of bisulfite adduct is as an aldehyde surrogate in a reductive amination reaction.

[015] The reported methods for the synthesis of ivacaftor suffered from several drawbacks such as harsh conditions, high temperature reactions and use of large excess of polyphosphoric acid and corrosive phosphoryl chloride etc. Furthermore, synthesis of ivacaftor requires use of high performance liquid chromatography (HPLC) techniques for the separation of ivacaftor and their analogues.

[016] Therefore, development of a simple and efficient synthetic route is in urgent need. Accordingly the present inventors developed environmentally benign, cost effective and short synthetic route for the synthesis of ivacaftor and their analogues.

Example 1:

Procedur A:

To a solution of indole acetic acid (500 mg, 2.85 mmol), aniline (2.85 mmol), HOBt (3.4 mmol) in acetonitrile (10 mL), EDC.HCl (3.4 mmol) followed by DIPEA (11.4 mmol) was added, and mixture was stirred for 16 h at ambient temperature. The

reaction mixture was evaporated to dryness, diluted with EtOAc (25 mL), washed with saturated aqueous NaHC03 solution (5 mL), H20 (5 mL), brine (5 mL), and dried over Na2S04. The crude material obtained after removal of solvent was purified by column chromatography (silica gel 230-400 mesh, ethyl acetate – pet ether) to afford corresponding amide as a colorless solid.

[040] Example 2:

2-(lH-indol-3-yl)-N-phenylacetamide (1) :

Yield: 570 mg; 80%; 1H NMR (200MHz, DMSO-d6) δ = 10.95 (brs, 1 H), 10.14 (s, 1 H), 7.64 (d, J = 7.8 Hz, 3 H), 7.47 – 7.24 (m, 4 H), 7.21 – 6.92 (m, 3 H), 3.76 (s, 2H); MS: 273 (M+Na)+.

[041] Example 3:

5-(2-(lH-indol-3-yl)acetamido)-2,4-di-tert-butylphenyl methyl carbonate (2): Yield: 800 mg; 64%; 1H NMR (200 MHz, DMSO-d6) δ = 11.51 (brs, 1 H), 9.41 (s, 1 H), 8.12 (d, J = 7.6 Hz, 1 H), 7.96 – 7.78 (m, 3 H), 7.71 – 7.42 (m, 3 H), 4.34 (s, 3 H), 4.30 (s, 2 H), 1.79 (s, 9 H), 1.64 (s, 9 H); MS: 459 (M+Na)+.

[042] Example 4:

(S)-2-(lH-indol-3-yl)-N-(l-phenylethyl)acetamide (3):

Yield: 620 mg; 78%; 1H NMR (400MHz ,DMSO-d6)5 = 10.88 (brs, 1 H), 8.48 (d, J = 8.1 Hz, 1 H), 7.59 (d, J = 7.8 Hz, 1 H), 7.39 – 7.26 (m, 5 H), 7.25 – 7.16 (m, 2 H), 7.08 (t, J = 7.3 Hz, 1 H), 7.02 – 6.95 (m, 1 H), 4.96 (t, J = 7.3 Hz, 1 H), 3.59 (s, 2H), 1.38 (d, J = 7.1 Hz, 3 H).

[043] Example 5:

N-(4-Fluorophenyl)-2-(lH-indol-3-yl)acetamide (4):

1H NMR (400 MHz, DMSO-d6) : δ 10.93 (brs, 1H), 10.17 (s, 1H), 7.68 – 7.61 (m, 3H), 7.36 (d, J= 8.1 Hz, 1H), 7.27 (d, J= 2.0 Hz, 1H), 7.15 – 7.13 (m, 3H), 7.11 – 6.99 (m, 1H), 3.73 (s, 2H); 13C NMR (100 MHz, DMSO-d6) : δ 170.1, 159.5, 157.1, 136.6, 136.3, 127.7, 124.4, 121.5, 121.3, 121.2, 119.1, 118.9, 115.8, 115.6, 111.8, 108.9, 34.2; MS: 269 (M+H)+

[044] Example 6:

N-(4-Chlorophenyl)-2-(lH-indol-3-yl)acetamide (5):

1H NMR (200 MHz, DMSO-d6): 510.93 (brs, 1H),10.24 (s, 1H), 7.67 – 7.59 (m, 3H), 7.36 – 7.27 (m, 4H), 7.12 – 6.98 (m, 2H), 3.74 (s, 2H); 13CNMR (100 MHz, DMSO-d6): 5170.4, 138.9, 136.7, 129.1, 127.8, 127.1, 124.5, 121.6, 121.2, 119.2, 119.0, 115.7, 111.9, 108.9, 34.3; MS: 285 (M+H)+.

[045] Example 7:

2-(lH-Indol-3-yl)-N-(p-tolyl)acetamide (6) :

1H NMR (400 MHz, DMSO-d6): 510.91 (brs, 1H), 10.01 (s, 1H), 7.62 (d, J= 7.8 Hz, 1H), 7.50 (d, J= 8.6 Hz, 2H), 7.37 (d, J= 8.1 Hz, 1H), 7.29 – 7.26 (m, 1H), 7.10 – 7.07 (m, 3H), 7.01 – 6.99 (m, 1H), 3.71 (s, 2H), 2.23 (s, 3H); 13C NMR (100 MHz, DMSO-de): 5170.0, 137.4, 136.6, 132.4, 129.5, 127.7, 124.3, 121.4, 119.6, 119.2, 118.8, 111.8, 109.1, 34.2, 20.9; MS: 265 (M+H)+.

[046] Example 8:

N-(4-Ethylphenyl)-2-(lH-indol-3-yl)acetamide (7):

XH NMR (400 MHz, DMSO-d6): 510.91 (brs, 1H), 10.01 (s, 1H), 7.61 (s, 1H), 7.52 (d, J= 8.3 Hz, 2H), 7.36 (d, J= 8.1 Hz, 1H), 7.26 (s, 1H), 7.15 – 7.04 (m, 3H), 6.99 (s, 1H), 2.55 (t, J= 7.5 Hz, 2H), 1.15 (t, J= 7.5 Hz, 3H); 13C NMR (100 MHz, DMSO-d6): 5169.9, 138.9, 137.6, 136.6, 128.3, 127.7, 124.3, 121.4, 119.6, 119.2, 118.8, 111.8, 109.1, 40.6, 40.4, 40.2, 40.0, 39.8, 39.6, 39.4, 34.2, 28.0, 16.2; MS: 279 (M+H)+.

[047] Example 9:

2-(lH-Indol-3-yl)-N-(4-propylphenyl)acetamide (8):

1H NMR (400 MHz, DMSO-d6): 58.48 (brs, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.50 – 7.42 (m, 2H), 7.33 – 7.15 (m, 6H), 7.07 (d, J= 8.3 Hz, 2H), 3.92 (s, 2H), 2.52 (t, J= 7.6 Hz, 2H), 1.65 – 1.53 (m, 2H), 0.91 (t, J= 7.3 Hz, 3H); 13C NMR (100 MHz, DMSO-d6): 5169.7, 138.9, 136.5, 135.2, 128.8, 126.9, 124.0, 122.8, 120.4, 120.1, 118.7, 111.6, 108.7, 37.4, 34.5, 24.6, 13.7; MS: 315 (M+Na)+.

[048] Example 10:

2-(lH-Indol-3-yl)-N-(4-isopropylphenyl)acetamide (9) :

yield 79% ; 1H NMR (400 MHz, DMSO-d6): δ 10.91 (brs, 1H), 10.01 (s, 1H), 7.62 (d, = 7.8 Hz, 1H), 7.55 – 7.49 (m, = 8.6 Hz, 2H), 7.37 (d, = 8.1 Hz, 1H), 7.26 (d, = 2.0 Hz, 1H), 7.18 – 7.11 (m, = 8.6 Hz, 2H), 7.11 – 7.05 (m, 1H), 7.02 – 6.95 (m, 1H), 2.95 – 2.71 (m, 1H), 1.17 (d, = 6.8 Hz, 6H); 13C NMR (100 MHz, DMSO-d6): δ 169.9, 143.5, 137.6, 136.6, 127.7, 126.8, 124.3, 121.4, 119.7, 119.2, 118.8, 111.8, 109.2, 24.4; MS: 315 (M+Na)+.

[049] Example 11:

2-(lH-indol-3-yl)-N-(4-(trifluoromethoxy)phenyl)acetamide (10):

Yield 85% ; 1H NMR (400 MHz, CDC13): δ 8.35 (brs., 1 H), 7.44 – 7.38 (m, 2 H), 7.27 – 7.21 (m, 3 H), 7.12 – 7.05 (m, 1H), 7.03 – 6.95 (m, 2H), 6.93 (d, = 8.6 Hz, 2H), 3.75 (s, 2H); 13C NMR (100 MHz, CDC13): δ 170.0, 145.3, 136.5, 136.2, 126.8, 124.1, 123.0, 121.6, 121.2, 120.5, 118.5, 111.7, 108.2, 34.4; MS: 335 (M+Na)+.

[050] Example 12:

N-(2-chloro-5-methoxyphenyl)-2-(lH-indol-3-yl)acetamide (11):

Yield 75% ; XH NMR (200 MHz, DMSO-d6): δ 10.98 (brs, 1H), 9.27 (s, 1H), 7.59 (d, = 7.8 Hz, 1H), 7.53 (d, = 2.9 Hz, 1H), 7.39 – 7.32 (m, 3H), 7.09 – 6.99 (m, 2H), 6.74 (dd, = 3.0, 8.8 Hz, 1H), 3.85 (s, 2H), 3.71 (s, 3H); 13C NMR (400 MHz, DMSO-d6): δ 170.4, 160.1, 141.1, 136.7, 130.0, 127.8, 124.4, 121.6, 119.2, 119.0, 111.9, 109.1, 105.4, 55.4, 34.4; MS: 315 (M+Na)+.

[051]Example 13:

N-(2-ethylphenyl)-2-(lH-indol-3-yl)acetamide (12):

Yield 78% ; 1H NMR (400 MHz, CDC13): δ 8.68 (brs, 1H), 7.95 (d, = 8.1 Hz, 1H), 7.67 (d, = 7.8 Hz, 1H), 7.48 – 7.44 (m, 2H), 7.29 – 7.23 (m, 1H), 7.22 – 7.20 (m, 3H), 7.05 (d, = 4.4 Hz, 2H), 2.00 (q, = 7.4 Hz, 2H), 0.67 (t, = 7.6 Hz, 3H); 13C NMR (100 MHz, CDC13): δ 169.9, 136.6, 135.0, 134.3, 128.7, 126.7, 125.1, 124.1, 123.0, 122.5, 120.4, 118.7, 111.6, 108.6, 34.4, 24.2, 13.6.

[052] Example 14:

N-(2-bromophenyl)-2-(lH-indol-3-yl)acetamide(13):

Yield 76%; 1H NMR (200 MHz, DMSO-d6): δ 11.00 (brs, 1H), 9.30 (s, 1H), 7.81 -7.77 (m, 1H), 7.63 – 7.56 (m, 2H), 7.41 – 7.35 (m, 3H), 7.11 – 7.05 (m, 3H), 3.85 (s, 2H);13C NMR (100 MHz, DMSO-d6): δ 169.9, 136.2, 132.5, 128.0, 127.2, 126.4, 125.5, 124.4, 121.2, 118.7, 118.5, 116.4, 111.4, 108.0, 33.2.

[053] Example 15:

N-benzyl-2-(lH-indol-3-yl)acetamide (14):

Yield 85%; 1H NMR (400 MHz, DMSO-d6): δ 10.89 (brs., 1H), 8.40 (t, = 5.7 Hz, 1H), 7.57 (d, = 7.8 Hz, 1H), 7.36 (d, = 8.1 Hz, 1H), 7.32 – 7.18 (m, 6H), 7.08 (t, = 7.5Hz, 1H), 7.03 – 6.90 (m, 1H), 4.28 (d, = 5.9Hz, 2H), 3.60 (s, 2H); 13C NMR (100 MHz, DMSO-de): δ 171.2, 140.1, 136.6, 128.7, 127.7, 127.2, 124.3, 121.4, 119.2, 118.7, 111.8, 109.3, 42.7, 33.2.

[054] Example 16:

2-(lH-indol-3-yl)-N-(4-methoxybenzyl)acetamide(15):

Yield 85% ; 1H NMR (400 MHz, DMSO-d6): δ 10.87 (brs, 1 H), 8.32 (t, = 5.6 Hz, 1 H), 7.55 (d, = 7.8 Hz, 1H), 7.35 (d, = 8.1 Hz, 1H), 7.22 – 7.13 (m, 3H), 7.11 – 7.05 (m, 1 H), 7.00 – 6.94 (m, 1H), 6.84 (d, = 8.6 Hz, 2H), 4.20 (d, = 6.1 Hz, 2H), 3.72 (s, 3H), 3.56 (s, 2H); 13C NMR (100 MHz, DMSO-d6): δ 171.1, 158.6, 136.6, 132.0, 129.0, 127.7, 124.2, 121.4, 119.2, 118.7, 114.1, 111.8, 109.4, 55.5, 42.1, 33.2.

[055] Example 17:

N,N-dibenzyl-2-(lH-indol-3-yl)acetamide (16):

Yield 70% ; 1H NMR (400 MHz, DMSO-d6): δ 10.91 (brs, 1H), 7.50 (d, = 7.8 Hz, 1H), 7.37 – 7.34 (m, 3H), 7.30 (d, = 6.6 Hz, 1H), 7.25 – 7.19 (m, 3H), 7.17 (t, = 6.6 Hz, 5H), 7.16 (d, = 7.8 Hz, 1H), 7.00 – 6.97 (m, 1H), 4.59 (s, 2H), 4.50 (s, 2H), 3.86 (s, 2H); 13C NMR (100 MHz, DMSO-d6): δ 171.7, 138.2, 136.6, 129.2, 128.8, 128.1, 127.8, 127.7, 127.5, 127.1, 124.2, 121.5, 119.2, 118.8, 111.8, 108.5, 50.7, 48.4, 31.2.

[056] Example 18:

2-(lH-indol-3-yl)-N-propylacetamide (17):

Yield 75% ; XH NMR (200 MHz, DMSO-d6): δ 10.86 (brs, 1H), 7.88 – 7.80 (m, 1H), 7.56 (d, = 7.6 Hz, 1H), 7.31 (d, = 7.8 Hz, 1H), 7.17 (d, = 2.3 Hz, 1H), 7.06 – 6.92 (m, 2H), 3.48 (s, 2H), 3.00 (q, J = 6.8 Hz, 2H), 1.39 (sxt, / = 7.2 Hz, 2H), 0.88 – 0.75 (t, = 7.2 Hz, 3H); 13C NMR (100 MHz, DMSO-d6): δ 171.0, 136.6, 127.8, 124.2,

121.4, 119.2, 118.7, 111.8, 109.6, 39.4, 33.3, 22.9, 11.9.

[057] Example 19:

N-hexyl-2-(lH-indol-3-yl)acetamide (18) :

Yield 87% ; 1H NMR (400 MHz, DMSO-d6): δ 10.84 (brs, 1H), 7.83 (brs, 1H), 7.54 (d, = 7.8 Hz, 1H), 7.33 (d, = 8.1 Hz, 1H), 7.21 – 7.13 (m, 1H), 7.06 (t, = 7.6 Hz, 1H), 6.96 (t, J = 7.5 Hz, 1H), 3.47 (s, 2H), 3.03 (q, / = 6.8 Hz, 2H), 1.37 (t, = 6.5 Hz, 2H), 1.30 – 1.15 (m, 6H), 0.84 (t, = 6.7 Hz, 3H); 13C NMR (100 MHz, DMSO-d6): δ 170.9, 136.6, 127.7, 124.2, 121.3, 119.1, 118.7, 111.7, 109.5, 39.06, 33.2, 31.5, 29.6, 26.5, 22.5, 14.4.

[058] Example 20:

Methyl (2-(lH-indol-3-yl)acetyl)-L-alaninate (19):

Yield 79% ; 1H NMR (400 MHz, CDC13): δ 8.53 (brs, 1H), 7.60 (d, = 7.8 Hz, 1H), 7.41 (d, = 8.1 Hz, 1H), 7.25 – 7.23 (m, 1H), 7.19 – 7.14 (m, 2H), 6.27 (d, = 7.3 Hz, 1H), 4.63 (t, = 7.3 Hz, 1H), 3.78 (s, 2H), 3.68 (s, 3H), 1.31 (d, = 7.3 Hz, 3H); 13C NMR (100 MHz, CDC13): δ 173.4, 171.2, 136.4, 127.0, 123.8, 122.5, 119.9, 118.7,

111.5, 108.5, 52.4, 48.0, 33.3, 18.2.

[059] Example 21:

-(6-chloro-lH-indol-3-yl)-N-phenylacetamide(20):

To a solution of 6-Chloro indole 20a (300 mg, 1.98 mmol )in anhydrous THF, Oxalyl chloride (186 μΤ, 276 mg, 2.18 mmol) was added and the mixture stirred at room temperature. After 2 h, N,N-Diisopropylethylamine (758 μΤ, 562 mg, 4.35 mmol) was

introduced to the mixture, followed by the aniline (221.0 mg, 2.37 mmol). The temperature was raised to 45 °C, and heating continued for 18 h. The solvent was evaporated, and then mixture was diluted with EtOAC (15 mL), washed with brine and dried over anhydrous Na2S04. The crude material obtained after removal of solvent was purified by column chromatography (10 – 20% EtOAc : Petroleum ether) to afford 20b (295 mg, 51% yield) as a yellow coloured solid. IR Omax(film): 3346, 3307,2853, 1724, 1678 cm“1; 1H NMR (400 MHz, DMSO-d6): δ 12.40 (br. s., 1H), 10.68 (s, 1H), 8.79 (d, = 3.2 Hz, 1H), 8.25 (d, = 8.6 Hz, 1H), 7.85 (d, = 7.8 Hz, 2H), 7.62 (d, = 1.7 Hz, 1H), 7.41 – 7.30 (m, 3H), 7.19 – 7.13 (m, 1H); 13C NMR (100 MHz, DMSO-d6): δ 182.5, 162.5, 140.0, 138.4, 137.4, 129.2, 128.5, 125.4, 124.8, 123.4, 122.9, 120.8, 113.0, 112.3; HRMS (ESI) Calculated for Ci6HnN2OCl[M+H]+: 299.0582, found 299.0580;

A solution of 20b (300 mg, 0.99 mmol) dissolved in MeOH (40 mL) was added to NaBH4 (45 mg, 1.23 mmol). The reaction was stirred for 4h and then added to saturated solution of Na2S04. The reaction mixture was further stirred for lh and then filtered through Celite.The filtrate obtained was concentrated in vacuo, and then mixture was diluted with EtOAc (15 mL), washed with brine and dried over anhydrous Na2S04. The crude material obtained after removal of solvent was forwarded for next step without further purification.In an N2 atmosphere, TMSC1 (1.272 mL, 9.9 mmol) in CH3CN (40 mL) was added to sodium iodide (1.488 mg, 9.9 mmol) and stirred for 2h. The reaction mixture was cooled to 0 °C and a solution of above crude alcohol (0.99 mmol) in CH3CN (10 mL) was then added drop wise over 30 min, followed by stirring for 3h. The reaction mixture was poured into NaOH (7g in 40 mL of water) and then extracted with ethyl acetate (15×2). The organic layer was washed with aq.Na2S203, dried over Na2S04 and concentrated in vacuo. The residue was chromatographed on silica gel (EtOAc:Pet ether) to afford 20 as a off white solid (two steps 38 % ); IR Umax(film): 3273, 3084,2953, 2857, 1629, 1562 cm“1; 1H NMR (400 MHz, DMSO-d6): δ 11.06 (br. s., 1H), 10.13 (br. s., 1H), 7.62 – 7.57 (m, 3H), 7.40 (s, 1H), 7.30 – 7.25 (m, 3H), 7.04 – 6.99 (m, 2H), 3.71 (s, 2H); 13C NMR (100 MHz, DMSO-d6): δ 170.1,

139.7, 136.9, 129.2, 126.5, 126.3, 125.5, 123.7, 120.6, 119.6, 119.3, 111.5, 109.4, 34.0; HRMS (ESI):Calculated for Ci6Hi4N2OCl[M+H]+: 285.0789, found 285.0786.

[060] Example 22:

2-(5-chloro-lH-indol-3-yl)-N-phenylacetamide(21):

21a 21b 21

To a solution of 5-Chloro indole 21a (300 mg, 1.98 mmol )in anhydrous THF(20 mL), Oxalyl chloride (186 ^L, 276 mg, 2.18 mmol) was added and the mixture stirred at room temperature. After 2 h, N,N-diisopropylethylamine (758 μΕ, 562 mg, 4.35 mmol) was introduced to the mixture, followed by the aniline (221.0 mg, 2.37 mmol). The tempera ture was raised to 45 °C, and heating continued for 18 h. The solvent was evaporated, and then mixture was diluted with EtOAC (15 mL), washed with brine and dried over anhydrous Na2S04. The crude material obtained after removal of solvent was purified by column chromatography (10 – 20% EtOAc : Petroleum ether) to afford (21b) (305 mg, 53% yield) as a yellow coloured solid. IR rjmax(film): 3346, 3307,2853, 1724, 1678 cm“1; 1H NMR (400 MHz, DMSO-d6): δ 12.40 (br. s., 1H), 10.68 (s, 1H), 8.79 (d, = 3.2 Hz, 1H), 8.25 (d, = 8.6 Hz, 1H), 7.85 (d, = 7.8 Hz, 2H), 7.62 (d, = 1.7 Hz, 1H), 7.42 – 7.30 (m, 3H), 7.20 – 7.14 (m, 1H); 13C NMR (100 MHz, DMSO-d6): δ 182.4, 162.4, 140.3, 138.4, 135.4, 129.2, 127.9, 124.8, 124.1, 120.8, 114.8, 112.0; HRMS (ESI) Calculated for Ci6HnN2OCl[M+H]+: 299.0582, found 299.0580; A solution of 21b (200 mg, 0.66 mmol) dissolved in MeOH (30 mL) was added to NaBH4 (30 mg, 0.82 mmol). The reaction was stirred for 4h and then added to saturated solution of Na2S04. The reaction mixture was further stirred for lh and then filtered through Celite. The filtrate obtained was concentrated in vacuo, and then mixture was diluted with EtOAc (15 mL), washed with brine and dried over anhydrous Na2S04. The crude material obtained after removal of solvent was forwarded for next step without further purification. In an N2 atmosphere, TMSC1 (848 mL, 6.6 mmol) in CH3CN (25 mL) was added to sodium iodide (992 mg, 6.6 mmol) and stirred for 2h. The reaction mixture was cooled to 0 °C and a solution of above crude alcohol(0.66 mmol) in CH3CN (5 mL) was then added dropwise over 30 min, followed by stirring for 3h. The reaction mixture was poured into NaOH (5g in 30 mL of water) and then extracted with ethyl acetate(15×2). The organic layer was washed with aq.Na2S203, dried over Na2S04 and concentrated in vacuo. The residue was chromatographed on silica gel (EtOAc:Pet ether) to afford 22 as a off white solid (two steps 42 % ); IR Umax(film): 3273, 3084,2955, 2857, 1629, 1562 cm“1; 1H NMR (400 MHz, DMSO-d6): δ 11.13 (br. s., 1H), 10.11 (s, 1H), 7.67 (s, 1H), 7.60 (d, = 7.8 Hz, 2H), 7.39 – 7.27 (m, 4H), 7.13 – 7.02 (m, 2H), 3.16 (s, 2H); 13C NMR (100 MHz, DMSO-d6): δ 169.9, 139.8, 135.0, 129.2, 128.9, 126.2, 123.6, 121.4, 119.6, 118.6, 113.4, 109.0, 34.0; HRMS (ESI) Calculated for Ci6H14N2OCl[M+H]+: 285.0789, found 285.0786.

[061] Example 23:

2-(l-benzyl-lH-indol-3-yl)-N-phenylacetamide (22):

Yield 79% ; 1H NMR (400 MHz, DMSO-d6): δ 7.67 (d, = 7.8 Hz, 1H), 7.54 (brs, 1H), 7.43 – 7.31 (m, 6H), 7.31 – 7.25 (m, 3H), 7.23 – 7.15 (m, 4H), 7.12 – 7.06 (m, 1H), 5.36 (s, 2H), 3.91 (s, 2H); 13C NMR (100 MHz, DMSO-d6): δ 169.7, 137.7, 137.2, 137.0, 128.9, 128.9, 127.9, 127.6, 126.9, 124.3, 122.7, 120.2, 119.9, 119.0, 110.2, 107.9, 77.4, 77.1, 76.8, 50.1, 34.5.

[062] Example 24:

Procedure B:

2-(lH-indol-3-yl)-N-phenylacetamidel(100 mg; 0.4 mmol) was dissolved in DCM:MeOH(50 mL; 5: 1), then a stream of 03 was passed through the solution until a blue color developed (10 min). The 03 stream was continued for 4 min. Then surplus O3 was removed by passing a stream of 02 through the solution for 10 min or until the blue colorcompletely vanished. Afterwards pyridine (0.1 mL;1.2mmol) was added to the cold (- 78 °C) mixture. The mixture was allowed to warm to room temperature (1 h) and then Et3N (0.35 mL; 2.4 mmol) were added. After stirring at room temperature overnight the reaction mass was concentrated under reduced pressure to dryness, diluted with EtOAc (30 mL), washed with H20 (5 mL), brine (5 mL), and dried over Na2S04. The crude material obtained after removal of solvent was purified by column chromatography (silica gel 230-400 mesh, MeOH – DCM) to give desired quinolone carboxamide as colorless solid.

[063] Example 25:

4-oxo-N-phenyl-l,4-dihydroquinoline-3-carboxamide (23):

Yield: 65 mg; 62%; XH NMR (200MHz ,DMSO-d6) δ = 12.97 (brs, 1 H), 12.49 (s, 1 H), 8.89 (s, 1 H), 8.33 (d, J = 8.2 Hz, 1 H), 7.91 – 7.69 (m, 4 H), 7.62 – 7.50 (m, 1 H), 7.37 (t, J = 7.8 Hz, 2 H), 7.18 – 7.01 (m, 1 H); MS: 287 (M+Na)+.

[064] Example 26:

2,4-di-tert-butyl-5-(4-oxo-l,4-dihydroquinoline-3-carboxamido)phenyl methyl carbonate (24):

Yield: 35 mg; 34%; 1H NMR (400MHz ,DMSO-d6) δ = 12.96 (brs, 1 H), 12.08 (s, 1 H), 8.94 – 8.82 (m, 1 H), 8.44 – 8.28 (m, 1 H), 7.86 – 7.79 (m, 1 H), 7.78 – 7.73 (m, 1 H), 7.59 (s, 1 H), 7.53 (t, J = 7.5 Hz, 1 H), 7.39 (s, 1 H), 3.86 (s, 3 H), 1.46 (s, 9 H), 1.32 (s, 9 H).

[065] Example 27:

(S)-4-oxo-N-(l-phenylethyl)-l,4-dihydroquinoline-3-carboxamide (25):

Yield: 56 mg; 53%; 1H NMR (500MHz ,DMSO-d6) δ = 12.75 (brs, 1H), 10.54 (d, J = 7.6 Hz, 1H), 8.73 (brs, 1H), 8.28 (d, J = 7.9 Hz, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.73 -7.68 (m, 1 H), 7.50 (t, J = 7.5 Hz, 1 H), 7.42 – 7.34 (m, 4 H), 7.29 – 7.23 (m, 1 H), 5.18 (t, J = 7.2 Hz, 1 H), 1.50 (d, J = 6.7 Hz, 3 H).

[066] Example 28:

Synthesis of ivacaftor (26):

To a solution of 2,4-di-tert-butyl-5-(4-oxo-l,4-dihydroquinoline-3-carboxamido)phenyl methyl carbonate 5 (30 mg, 0.06mmol) in MeOH (2 mL) was added NaOH (5.3 mg, 0.13mmol) dissolved in H20 (2 mL), and the reaction mixture was stirred at room temperature for 5h. Reaction mass was evaporated to one third of its volume (temperature not exceeding 40°C) and acidified with aq.2N HC1 to pH 2-3. The resulting precipitate was collected by suction filtration give desired compound 7 (19 mg, 76%) as off white solid H NMR (400MHz ,DMSO-d6) δ = 12.88 (d, J = 6.6 Hz, 1 H), 11.81 (s, 1 H), 9.20 (s, 1 H), 8.86 (d, J = 6.6 Hz, 1 H), 8.32 (d, J = 7.8 Hz, 1 H), 7.88 – 7.65 (m, 2 H), 7.51 (t, J = 7.5 Hz, 1 H), 7.16 (s, 1 H), 7.10 (s, 1 H), 1.38 (s,9H), 1.36 (s, 9H).

[067] Example 29:

N-(4-fluorophenyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide (27):

Yield 56% ; 1H NMR (400 MHz, DMSO-d6): δ 12.96 (br. s., 1H), 12.50 (s, 1H), 8.88 (s, 1H), 8.33 (d, = 7.3 Hz, 1H), 7.86 – 7.72 (m, 4H), 7.54 (t, = 7.3 Hz, 1H), 7.20 (t, = 8.8 Hz, 2H); 13C NMR (400 MHz, DMSO-d6): δ 176.8, 163.2, 159.7, 157.3, 144.6, 139.6, 135.7, 133.5, 126.4, 125.9, 125.8, 121.8, 119.7, 116.1, 115.9, 110.9.

[068] Example 30:

N-(4-chlorophenyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide (28):

Yield 51% ; 1H NMR (400 MHz, DMSO-d6): δ 13.00 (brs., 1H), 12.59 (br. s., 1H), 8.89 (s, 1H), 8.34 (d, = 7.6 Hz, 1H), 7.83 – 7.76 (m, 4H), 7.56 (s, 1H), 7.42 (d, = 7.9 Hz, 2H); 13C NMR (400 MHz, DMSO-d6): δ 176.8, 163.4, 144.7, 139.6, 138.2, 133.5, 129.4, 127.4, 126.4, 125.9, 125.8, 121.6, 119.7, 110.8.

[069] Example 31:

4-oxo-N-(p-tolyl)-l,4-dihydroquinoline-3-carboxamide (29):

Yield 57% ; 1H NMR (400 MHz, DMSO-d6): δ 12.94 (brs., 1H), 12.40 (s, 1H), 8.88 (s, 1H), 8.33 (d, = 7.8Hz, 1H), 7.82 – 7.80 (m, 1H), 7.76 – 7.7 (m, 1H), 7.63 (d, = 8.3 Hz, 2H), 7.53 (t, = 7.3 Hz, 1H), 7.17 (d, = 8.1 Hz, 2H), 2.29 (s, 3H); 13C NMR (100 MHz, DMSO-de): δ 176.8, 163.1, 144.5, 139.6, 136.8, 133.4, 132.8, 129.9, 126.4, 125.9, 125.7, 120.0, 119.6, 111.1, 20.9; HRMS (ESI):Calculated for Ci7H1502N2[M+H]+: 279.1128, found 279.1127.

[070] Example 32:

N-(4-ethylphenyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide (30):

Yield 51% ; 1H NMR (400 MHz, DMSO-d6): δ 12.95 (br. s., 1H), 12.40 (d, = 7.8 Hz, 1H), 8.87 (d, = 6.1 Hz, 1H), 8.33 (d, = 8.1 Hz, 1H), 7.81 – 7.76 (m, 2H), 7.66 – 7.62 (m, = 8.3 Hz, 2H), 7.53 (t, 7 = 7.5 Hz, 1H), 7.22 – 7.17 (m, = 8.3 Hz, 2H), 2.58 (q, = 7.6 Hz, 2H), 1.18 (t, = 7.6 Hz, 3H); 13C NMR (400 MHz, DMSO-d6): δ 181.5, 167.8, 149.3, 144.3, 144.0, 141.7, 138.2, 133.4, 131.1, 130.7, 130.5, 124.8, 124.4, 115.9, 32.8, 20.9.

[071] Example 33:

4-Oxo-N-(4-propylphenyl)-l,4-dihydroquinoline-3-carboxamide (31):

Yield 51%; 1H NMR (500 MHz, DMSO-d6): δ12.93 (brs, 1H), 12.40 (s, 1H), 8.87 (s, 1H), 8.36 – 8.29 (m, 1H), 7.86 – 7.78 (m, 1H), 7.75 (d, J= 7.9 Hz, 1H), 7.68 – 7.61 (m, J= 8.2 Hz, 2H), 7.54 (t, J= 7.6 Hz, 1H), 7.22 – 7.14 (m, J= 8.2 Hz, 2H), 2.55 – 2.51 (m, 2H), 1.64 – 1.53 (m, 2H), 0.90 (t, J= 7.3 Hz, 3H); 13C NMR (500 MHz, DMSO-d6): 176.8, 163.1, 144.5, 139.6, 137.6, 137.0, 133.5, 129.3, 126.4, 125.9, 125.7, 120.0, 119.7, 111.1, 37.2, 24.6, 14.1.

[072] Example 34:

N-(4-isopropylphenyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide (32):

Yield 46% ; 1H NMR (500 MHz, DMSO-d6): δ 12.93 (br. s., 1H), 12.40 (br. s., 1H), 8.89 – 8.86 (m, 1H), 8.33(d, = 7.6 Hz, 1H), 7.81 – 7.50 (m, 5H), 7.25 – 7.21 (m, 2H), 2.90-2.83 (m, 1H), 1.22-1. l l(m, 6H); 13C NMR (100 MHz, DMSO-d6): δ 176.8, 163.1, 144.5, 143.9, 139.6, 137.1, 133.4, 127.2, 126.4, 125.9, 125.7, 120.1, 119.6, 111.1, 33.4, 24.4.

[073] Example 35:

4-oxo-N-(4-(trifluoromethoxy)phenyl)-l,4-dihydroquinoline-3-carboxamide(33):

Yield 57% ; 1H NMR (400 MHz, DMSO-d6): δ 12.98 (br. s., 1H), 12.63 (s, 1H), 8.88 (d, = 4.9 Hz, 1H), 8.32 (d, = 7.8 Hz, 1H), 7.89 – 7.83 (m, = 8.8 Hz, 2H), 7.79 (d, = 7.6 Hz, 1H), 7.77 – 7.73 (m, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.40 – 7.34 (m, = 8.6 Hz, 2H); 13C NMR (100 MHz, DMSO-d6): δ 176.8, 163.5, 144.7, 144.0, 139.5, 138.5, 133.5, 126.3, 125.9, 125.8, 122.3, 121.4, 119.7, 110.7.

[074] Example 36:

N-(2-chloro-5-methoxyphenyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide(34):

Yield 54% ; XH NMR (400 MHz, DMSO-d6): δ 12.98 (br. s., 1H), 12.49 (s, 1H), 8.88 (s, 1H), 8.33 (d, = 7.8 Hz, 1H), 7.83 – 7.75 (m, 1H), 7.56-7.48 (m, 3H), 7.27 – 7.21 (m, 1H), 6.67 (d, = 7.8 Hz, 1H), 3.77 (s, 3H); 13C NMR (400 MHz, DMSO-d6): δ 176.8, 163.4, 160.2, 144.7, 140.4, 139.6, 133.5, 130.3, 126.4, 125.9, 125.8, 119.7, 112.3, 111.0, 109.5, 105.7, 55.5.

[075] Example 37:

N-(2-ethylphenyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide(35):

Yield 58% ; 1H NMR (400 MHz, DMSO-d6): δ 12.94 (br. s., 1H), 12.37 (s, 1H), 8.90 (s, 1H), 8.36 (dd, = 8.1, 1.4 Hz, 2H), 8.32 (dd, = 8.1, 1.4 Hz, 2H), 7.82 – 7.74 (m, 1H), 7.53- 7.19 (m, 3H), 7.15 – 7.06(m, 1H), 2.79 (q, = 7.3 Hz, 2H), 1.26 (t, = 7.5 Hz, 3H); 293 (M+H)+.

[076] Example 38:

N-(2-bromophenyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide(36):

Yield 47% ; 1H NMR (200 MHz, DMSO-d6): δ 12.98 (br. s., 1H), 12.69 (s, 1H), 8.90 (d, = 5.9 Hz, 1H), 8.54 (dd, 7 = 1.4, 8.3 Hz, 1H), 8.34 (d, = 7.6 Hz, 1H), 7.86 – 7.67 (m, 3H), 7.57 – 7.49 (m, 1H), 7.40 (t, = 7.2 Hz, 1H), 7.10 – 7.05 (m, 1H); 13C NMR (100 MHz, DMSO-de): δ 176.7, 163.7, 145.0, 139.5, 137.7, 133.5, 133.1, 128.6, 126.4, 126.0, 125.8, 125.3, 122.9, 119.7, 113.4, 110.8.

[077] Example 39:

N-benzyl-4-oxo-l,4-dihydroquinoline-3-carboxamide(37):

Yield 58% ; 1H NMR (400 MHz, CD3OD-d6): δ 8.82 (s, 1 H), 8.35 (d, = 8.1 Hz, 1 H), 7.79 – 7.77 (m, 1 H), 7.65 (d, = 8.3 Hz, 1 H), 7.52 (t, = 7.6 Hz, 1 H), 7.42 – 7.34 (m, 4 H), 7.31 – 7.26 (m, 1 H), 4.67 (s, 2 H); 13C NMR (400 MHz, DMSO-d6): δ 176.6, 165.0, 144.2, 140.0, 139.5, 133.2, 128.9, 128.7, 127.8, 127.3, 126.6, 125.9, 125.4, 119.5, 111.2, 42.6.

[078] ] Example 40:

N-(4-methoxybenzyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide(38):

Yield 56% ; 1H NMR (400 MHz, DMSO-d6): δ 12.73 (br. s., 1H), 10.35 (t, = 5.3 Hz, 1H), 8.78 (d, = 6.1 Hz, 1H), 8.24 (d, = 8.1 Hz, 1H), 7.76 (d, = 7.1 Hz, 1H), 7.73 -7.68 (m, 1H), 7.48 (t, = 7.5 Hz, 1H), 7.28 (d, = 8.3 Hz, 2H), 6.91 (d, = 8.1 Hz, 2H), 4.49 (d, = 5.6 Hz, 2H), 3.74 (s, 3H); 13C NMR (100 MHz, DMSO-d6): δ 176.6, 164.8, 158.8, 144.1, 139.5, 133.1, 131.9, 129.2, 126.6, 125.8, 125.4, 119.5, 114.3, 111.3, 55.5, 42.0.

[079] Example 41:

N,N-dibenzyl-4-oxo-l,4-dihydroquinoline-3-carboxamide(39):

Yield 43% ; 1H NMR (400 MHz, DMSO-d6): δ 12.21 (br. s., 1H), 8.27 (d, = 4.9 Hz, 1H), 8.21 (d, = 7.6 Hz, 1H), 7.49 – 7.41 (m, 2H), 7.41 – 7.35 (m, 3H), 7.33 – 7.20 (m, 5H), 7.20 – 7.11 (m, 7 = 7.1 Hz, 2H), 4.59 (br. s., 2H), 4.42 (s, 2H).

[080] Example 42:

4-oxo-N-propyl-l,4-dihydroquinoline-3-carboxamide(40):

Yield 47% ;1H NMR (400 MHz, DMSO-d6): δ 12.7 (br.s., 1H)10.05 (t, = 5.5 Hz, 1H), 8.74 (s, 1H), 8.26 (d, = 8.1 Hz, 1H), 7.83 – 7.66 (m, 2H), 7.52 – 7.44 (m, 1H), 3.33 – 3.22 (m, 2H), 1.61 – 1.49 (m, 2H), 0.93 (t, = 7.5 Hz, 3H); 13C NMR (100 MHz, DMSO-de): δ 176.6, 164.8, 143.9, 139.5, 133.1, 126.6, 125.9, 125.3, 119.4, 111.4, 39.3, 23.1, 12.0

[081] Example 43:

N-hexyl-4-oxo-l,4-dihydroquinoline-3-carboxamide(41):

Yield 51% ;1H NMR (400 MHz, DMSO-d6): δ 12.68 (m, 1H), 10.02 (t, = 5.5 Hz, 1H), 8.73 (d, = 6.1 Hz, 1H), 8.27 – 8.25 (m, 1H), 7.77 – 7.67 (m, 2H), 7.47 (t, = 7.5 Hz, 1H), 3.33 – 3.29 (m, 2H), 1.56 – 1.45 (m, 2H), 1.34 – 1.25 (m, 6H), 0.88 – 0.82 (m, 3H); 13C NMR (100 MHz, DMSO-d6): δ 176.6, 164.8, 143.9, 139.5, 133.1, 126.6, 125.9, 125.3, 119.4, 111.4, 38.7, 31.5, 29.8, 26.7, 22.5, 14.4.

[082] Example 44:

Methyl (4-oxo-l,4-dihydroquinoline-3-carbonyl)-L-alaninate(42):

Yield 38% ; 1H NMR (400 MHz, CD3OD): δ 8.74 (s, 1H), 8.47 – 8.29 (m, 1H), 7.86 -7.76 (m, 1H), 7.64 (d, = 8.3 Hz, 1H), 7.58 – 7.44 (m, 1H), 4.69 (d, = 7.3 Hz, 1H), 3.79 (s, 3H), 1.55 (d, = 7.3 Hz, 3H); 13C NMR (100 MHz, CD3OD): δ 177.3, 173.3, 165.5, 143.6, 139.2, 132.9, 126.3, 125.4, 125.2, 118.5, 110.3, 51.5, 47.0, 17.0.

[083] Example 45:

7-chloro-4-oxo-N-phenyl-l,4-dihydroquinoline-3-carboxamide(43):

Yield 48% ; IR Omax(film): 2920, 2868, 1661, 1601 cm” 1; 1H NMR (400 MHz, DMSO-de): δ 12.91 (br. s., 1H), 12.30 (s, 1H), 8.90 (s, 1H), 8.29 (d, = 8.8 Hz, 1H), 7.80 -7.67 (m, 3H), 7.58 – 7.51 (m, 1H), 7.36 (t, = 7.7 Hz, 2H), 7.09 (t, = 7.3 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ 176.3, 162.9, 145.4, 140.3, 139.2, 138.0, 129.5, 128.2, 126.1, 125.1, 123.9, 120.1, 118.8, 111.6.

[084] Example 46:

6-chloro-4-oxo-N-phenyl-l,4-dihydroquinoline-3-carboxamide(44):

Yield 52% ; 1H NMR (400 MHz, DMSO-d6): δ 13.05 (brs, 1H), 12.27 (s, 1H), 8.88 (s, 1H), 8.21 (d, = 2.2 Hz, 1H), 7.86 – 7.67 (m, 4H), 7.36 (t, = 7.8 Hz, 2H), 7.16 – 7.04 (m, 1H); 13C NMR (100 MHz, DMSO-d6): δ 175.6, 162.9, 144.9, 139.1, 138.2, 133.5, 130.4, 129.5, 127.5, 124.9, 123.9, 122.0, 120.1, 111.4.

[085] Example 47:

l-benzyl-4-oxo-N-phenyl-l,4-dihydroquinoline-3-carboxamide(45)

Yield 55% ; 1H NMR (400 MHz, DMSO-d6): δ 12.30 (s, 1H), 9.05 (s, 1H), 8.60 (dd, = 1.7, 8.1 Hz, 1H), 7.82 (d, = 7.8 Hz, 2H), 7.69 – 7.62 (m, 1H), 7.55 – 7.45 (m, 2H), 7.43 – 7.34 (m, 5H), 7.24 – 7.18 (m, 2H), 7.17 – 7.10 (m, 1H), 5.53 (s, 2H); 13C NMR (100 MHz, DMSO-d6): δ 176.9, 162.9, 148.7, 139.3, 138.7, 134.1, 133.1, 129.4, 128.9, 128.7, 128.0, 127.4, 126.2, 125.5, 123.9, 120.5, 116.9, 112.3, 57.9; HRMS (ESI): Calculated for C23H1802N2Na [M+Na]+: 377.1260, found 377.1259; MS: 355 (M+H)+.

[086] Advantages of invention:

1. Cost-effective process for synthesis.

2. Carried out at environmentally benign conditions.

3. Short synthetic route.

4. Useful for making several related compounds of medicinal

 

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DR SRINIVASA REDDY recieving NASI – Reliance Industries Platinum Jubilee Award (2015) for Application Oriented Innovations in Physical Sciences.

 

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MYSELF WITH HIM

 

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From left to right: Dr. D. Srinivasa Reddy, Shri Y. S. Chowdary, Dr. Harsh Vardhan, Dr. Girish Sahni

  • Dr D. Srinivasa Reddy receiving the prestigious “SHANTI SWARUP BHATNAGAR” award at the occasion of the 75th Foundation day of CSIR.

Shanti Swarup Bhatnagar awardees with the honorable Prime Minister of India

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NCL PUNE

DSR Group

//////////WO-2016181414, WO 2016181414,  IVACAFTOR, new patent, COUNCIL OF SCIENTIFIC & INDUSTRIAL RESEARCH,  Anusandhan Bhawan, Rafi Marg New Delhi, INDIA, CSIR, Dr. D. Srinivasa Reddy

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Now online – Stimuli article on the proposed USP General Chapter “The Analytical Procedure Lifecycle <1220>“

 regulatory  Comments Off on Now online – Stimuli article on the proposed USP General Chapter “The Analytical Procedure Lifecycle <1220>“
Nov 222016
 

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Now online – Stimuli article on the proposed USP General Chapter “The Analytical Procedure Lifecycle <1220>”
A Stimuli Article to the Revision Process regarding the proposed New USP General Chapter “The Analytical Procedure Lifecycle <1220>” has been published. Read more about the new concept for the lifecycle managment of analytical methods.

http://www.gmp-compliance.org/enews_05629_Now-online—Stimuli-article-on-the-proposed-USP-General-Chapter-%22The-Analytical-Procedure-Lifecycle–1220-%22_15438,Z-PDM_n.html

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The General Chapters—Chemical Analysis Expert Committee is currently developing a new general chapter <1220> The Analytical Procedure Lifecycle. The purpose of this new chapter will be to more fully address the entire procedure lifecycle and define concepts that may be useful.

A Stimuli article on the proposed General Chapter <1220> has been approved for publication in Pharmacopeial Forum 43(1) [Jan.-Feb. 2017]. USP is providing this Stimuli article in advance of its publication to provide additional time for comments.

In addition to offering a preview of the proposed general chapter, the General Chapters—Chemical Analysis Expert Committee and the Validation and Verification Expert Panel are seeking specific input from users in the pharmaceutical industry regarding the following questions:

  • Would a general chapter on the lifecycle approach be valuable?
  • Is the information presented herein sufficient for implementation of an analytical procedure under the quality by design (QbD) approach?
  • Would incorporation of references to statistical tools, either in this chapter or in another chapter, be valuable?
  • Can you provide input or approaches that would improve this proposed general chapter?

The content and scope of the proposed general chapter will be refined on the basis of responses to this Stimuli article. Because stakeholders may have differing views, the objective of this Stimuli article is to identify and build areas of consensus that may be included in <1220>.

The approach is consistent with the concept of quality by design (QbD) as described in International Council for Harmonisation (ICH) Q8-R2, Q9, Q10, and Q11.

In order to provide a holistic approach to controlling an analytical procedure throughout its lifecycle, one can use a three-stage concept that is aligned with current process validation terminology:

  • Stage 1: Procedure Design and Development (Knowledge Gathering, Risk Assessment, Analytical Control Strategy, Knowledge Management, Preparing for Qualification)
  • Stage 2: Procedure Performance Qualification
  • Stage 3: Continued Procedure Performance Verification (Routine Monitoring, Changes to an Analytical Procedure)

A fundamental component of the lifecycle approach to analytical procedures is having a predefined objective that stipulates the performance requirements for the analytical procedure. These requirements are described in the analytical target profile (ATP) which can be considered as analogous to the quality target product profile (QTPP).

The Download Stimuli Article is available on the USP website since October 14, 2016: Proposed New USP General Chapter: The Analytical Procedure Lifecycle <1220>.

Comments will be accepted until March 31, 2017, the end of the comment period for Pharmacopeial Forum 43(1). This Stimuli article provides the framework for the proposed general chapter “The Analytical Procedure Lifecycle <1220>” and describes the current thinking of the USP Validation and Verification Expert Panel which advises the General Chapters—Chemical Analysis Expert Committee with regard to future trends in analytical procedures development, qualification, and continued monitoring.

 

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/////////////Stimuli article, proposed USP General Chapter, The Analytical Procedure Lifecycle,  <1220>

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Opportunities for Reducing Sampling and Testing of Starting Materials

 regulatory  Comments Off on Opportunities for Reducing Sampling and Testing of Starting Materials
Nov 222016
 

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Chapter 5 of the EC GMP Guide for the area of production was updated last year. This chapter contains concrete information about the conditions when testing and sampling of APIs and excipients can be reduced. Read more here about the sections 5.35 and 5.36 of the EU GMP Guide.

http://www.gmp-compliance.org/enews_05655_Opportunities-for-Reducing-Sampling-and-Testing-of-Starting-Materials_15461,15911,15462,Z-QCM_n.html

Chapter 5 of the EC GMP Guide for the area of production was already updated last year. However, not everybody really knows that it contains concrete information about the conditions when testing and sampling of APIs and excipients can be reduced. Particularly sections 5.35 and  5.36 include requirements and thus show possibilities for a reduction.

Basically, the manufacturers of finished products are responsible for every testing of starting materials as described in the marketing authorisation dossier. Yet, part of or complete test results from the approved starting material manufacturer can be used, but at least their identity has to be tested – as described in the in the marketing authorisation dossier.

If one chooses to outsource the testing activity to the supplier, this has to be justified and documented. Moreover, a few additional measures have to be fulfilled, like:

  • Particular attention should be paid to the distribution controls (transport, wholesaling, storage, delivery) to ensure that ultimately the test results are still applicable to the delivered material.
  • Performance of risk-based audits at the sites executing the testing and sampling of starting materials to verify the GMP compliance and to ensure that the specifications and testing methods are used as described in the marketing authorisation dossier.
  • The certificate of analysis of the manufacturer/supplier of the starting material should be signed by a designated person with appropriate qualifications and experience. The signature confirms the compliance with the agreed product specification.
  • The medicinal product manufacturer should have adequate experience in dealing with the starting material manufacturer – including assessment of batches previously received and the history of compliance before reducing own, internal testing.
  • At appropriate intervals, the medicinal product manufacturer or another approved contract laboratory has to carry out a full analysis to compare the test results with the results of the certificate of analysis of the material manufacturer or supplier, and thus to check their reliability. In case of discrepancy, an investigation has to be performed and appropriate measures taken. The certificates of analysis cannot be accepted until those measures are completed.

You can access the complete Chapter 5 “Production” of the EU GMP Guide here.
////////Opportunities,  Reducing,  Sampling, Testing, Starting Materials, EC GMP Guide

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