Webinars:

1. An Efficient Synthesis of (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 5-hydroxy-1,3-oxathiolane-2-carboxylate: A Key Intermediate in the Synthesis of Lamivudine and Emtricitabine

2. An Economical Route to Lamivudine and Emtricitabine Featuring a Novel Strategy for Stereospecific Assembly

WEBINAR DATE: April 7th, 2020 REGISTRATION:https://medicines4all.vcu.edu/lamivudine-emtricitabine-webinar/ 

The Medicines for All Institute’s (M4ALL’s) mission is to improve access to affordable medicines by reducing the cost of active pharmaceutical ingredients (APIs) and key raw materials which can be major cost drivers in treating infectious diseases in the developing world. M4ALL has demonstrated cost-effective processes for APIs, starting materials, and key intermediates for many critical medicines, with funding from the Bill & Melinda Gates Foundation.

In support of M4ALL’s mission, M4ALL will host 2 webinars to introduce our research on efficient and economical syntheses of (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 5-hydroxy-1,3-oxathiolane-2-carboxylate: A Key Intermediate in the Synthesis of Lamivudine and Emtricitabine on April 7th, 2020. Participants may register for the webinars through the registration website until April 7th.

The purpose of the first webinar is to provide technical information on M4ALL’s one-pot protocol for the preparation of (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 5-hydroxy-1,3-oxathiolane-2-carboxylate from high volume, low-cost raw materials.A simple process affords the hydroxyoxathiolane intermediate that can be converted into either lamivudine or emtricitabine. This intermediate is currently sold at $34/kg. M4All’s process is projected to produce this material at less than $27/kg. If the projected savings are realized, this should translate to approximately a $18/kg savings for lamivudine and emtricitabine. We project that this process, implemented at scale, could result in a cost of lamivudine API at ~$120-$125/kg and a cost of emtricitabine API at ~$165-170/kg. M4ALL will release a process development report in April 2020. In the second webinar M4ALL will showcase a fully revised synthesis featuring a novel strategy for stereospecific assembly. This next generation synthesis features simple, inexpensive, and readily available raw materials. Reduction of the penultimate intermediate leading to lamivudine is highly efficient due to its low molecular weight in comparison to the incumbent intermediate. This is a driver for lower cost of goods and increased material throughput. The current cost of goods is estimated to be $112/kg as compared to the current market price of $140-145/kg. With optimization of these preliminary results CoGs can potentially be further decreased. Our objective is to encourage interested parties to adopt our improved technologies.

Market Summary:All high-volume ARV regimens contain lamivudine or emtricitabine; both APIs are also included in many second-line, pediatric, PEP and PrEP formulations. The market for lamivudine is conservatively projected to reach 2000 MT by 2023.

Administrative:All administrative and technical questions should be directed to: m4all@vcu.edu. Please refer to the notice number (M4ALL-3TC-2020-1) in all correspondences. This announcement is not a request for proposals. M4ALL will not provide reimbursement for costs incurred in responding to this notice. Respondents are advised that M4ALL will respond within 48 hours.

Publication: Toward Secure Supply of Remdesivir via a 2 Pot Triazine Synthesis: Supply Centered Synthesis

TECHNICAL POC: Dr. David Snead, Director of Research

Publication: The Medicines for All Institute’s (M4ALL’s) mission is to improve access to affordable medicines by reducing the cost of active pharmaceutical ingredients (APIs) and key raw materials which can be major cost drivers in treating infectious diseases in the developing world. M4ALL has demonstrated cost-effective processes for APIs, starting materials, and key intermediates for many critical medicines, with funding from the Bill & Melinda Gates Foundation.

In support of M4ALL’s mission, M4ALL has published a manuscript to introduce our research “Toward Secure Supply of Remdesivir via a 2-Pot Triazine Synthesis: Supply Centered Synthesis.”. The purpose of this publication is to provide technical information on M4ALL’s two-pot protocol for the preparation of pyrrolotriazine. This route features atom economy and reduced derivatization of starting materials, by making use of highly abundant, commoditized raw material inputs. The yield of triazine was doubled from 33% to 59%, and the synthetic step count was reduced from 4 to 2. A one-pot cascade sequence was developed for direct cyanation of pyrrole, and the problematic nature of typically dilute electrophilic aminations was solved with semi-continuous processing. Moreover, development of a continuous platform afforded access to the ideal yet non-commercial aminating reagent, monochloramine. Unit operations are minimized by telescoping reactions. These efforts help to secure the Remdesivir supply chain. Our objective is to encourage interested parties to adopt our improved technologies. The publication is available on ChemRxiv.

Market Summary: As of August 2020, the WHO reports that there are over 19 million cases of COVID-19 and over 727,000 deaths worldwide, with additional cases expected. Remdesivir is currently undergoing multiple phase 3 trials globally and is approved for use in several countries.

Administrative: All administrative and technical questions should be directed to: m4all@vcu.edu. Please refer to the notice number (M4ALL-REM-2020-1) in all correspondences. This announcement is not a request for proposals. M4ALL will not provide reimbursement for costs incurred in responding to this notice. Respondents are advised that M4ALL will respond within 48 hours.

Open-Access Publication: An Alternative Approach to the Synthesis of PMPA: A Key Intermediate in the Synthesis of Tenofovir Disoproxil Fumarate and Tenofovir Alafenamide Fumarate

The Medicines for All Institute’s (M4ALL’s) mission is to improve access to affordable medicines by reducing the cost of active pharmaceutical ingredients (APIs) and key raw materials which can be major cost drivers in treating infectious diseases in the developing world. With funding from the Bill & Melinda Gates Foundation, M4ALL has demonstrated cost-effective processes for APIs, starting materials, and key intermediates for many critical medicines.

In support of M4ALL’s mission, M4ALL published a manuscript to describe our research on “An Alternative Approach to the Synthesis of PMPA: A Key Intermediate in the Synthesis of Tenofovir Disoproxil Fumarate and Tenofovir Alafenamide Fumarate” in ChemRxiv. The purpose of this open-access publication is to provide technical information on M4ALL’s two-step preparation of (R)-(((1-(6-amino-9H-purin-9yl)propan-2-yl)oxy)methyl)phosphonic acid (PMPA) from high volume, low-cost raw materials. A simple process affords the phosphonic acid intermediate that can be converted into either tenofovir disoproxil fumarate or tenofovir alafenamide fumarate. This intermediate is currently manufactured via a three-stage process beginning with adenine. There are couple of challenges associated with the typical in-market process including material lost due to N-alkylation of the adenine starting material and material lost upon filtration. M4All’s process avoids the N-alkylation issue and improves the processability of the synthesis. M4All’s synthesis has a lower number of unit operations, reduced processing time and a lower waste-to-drug mass ratio when compared to typical manufacturing processes for PMPA. Our objective is to encourage interested parties to adopt our improved technologies.  

Market Summary: The market for tenofovir disoproxil fumarate is conservatively projected to reach 1900 MT by 2022.^[1]

Administrative: All administrative and technical questions should be directed to: m4all@vcu.edu. Please refer to the notice number (M4ALL-TDF-2020-1) in all correspondences. This announcement is not a request for proposals. M4ALL will not provide reimbursement for costs incurred in responding to this notice. Respondents are advised that M4ALL will respond within 48 hours.

Webinar: Efficient Synthesis of Complex Pyridone Intermediates: A Dolutegravir Starting Material Is Prepared as an Exemplar

The Medicines for All Institute’s (M4ALL’s) mission is to improve access to affordable medicines by reducing the cost of active pharmaceutical ingredients (APIs) and key raw materials which can be major cost drivers in treating infectious diseases in the developing world.  In collaboration with the Bill & Melinda Gates Foundation, M4ALL has demonstrated cost-effective processes for APIs, starting materials, and key intermediates for many critical medicines. In support of M4ALL’s mission, M4ALL will host a webinar to introduce our research on “Continuous Synthesis of the Pyridone In Route to Dolutegravir” on June 11, 2019.  Participants must register for the webinar through the registration website by June 11, 2019.  The purpose of this webinar is to provide technical information on M4ALL’s recently developed continuous flow pyridone synthesis. The process is flexible and should have application towards a few APIs, including cabotegravir and bictegravir. Our objective is to encourage interested parties to adopt our technology. M4ALL recently reported a continuous synthesis of Dolutegravir (Ziegler, et al. ACIEE 2018) wherein an intensified and generalizable continuous synthesis of complex pyridones was described. Since this report, we have continued to improve the approach. Using Dolutegravir as an example, we compare our continuous process to the previous patented batch process.

M4ALL will release a process development report in June 2019 upon request.

Market Summary: According to the CHAI HIV Market Report, Issue 9 (September 2018) the market for dolutegravir API is conservatively projected as 50 MT in 2019, 100 MT in 2020, 150 MT in 2021 and 200 MT in 2022.

Administrative: All administrative and technical questions should be directed to m4all@vcu.edu. Please refer to the notice number (M4ALL-DTG-2019-1) in all correspondences. This announcement is not a request for proposals. M4ALL will not provide reimbursement for costs incurred in responding to this notice. Respondents are advised that M4ALL will respond within 48 hours.

Note: M4ALL will be attending CPhI China in Shanghai during June 18-20, 2019. If interested in meeting with M4ALL at CPhI, please contact Dr. Rodger Stringham at rwstringham@vcu.edu.

Webinar: An Efficient Synthesis of (R)-3-aminobutanol: A Significant Cost Driver in the Synthesis of Dolutegravir

The Medicines for All Institute’s (M4ALL’s) mission is to improve access to affordable medicines by reducing the cost of active pharmaceutical ingredients (APIs) and key raw materials which can be major cost drivers in treating infectious diseases in the developing world. In collaboration with the Bill & Melinda Gates Foundation, M4ALL has demonstrated cost-effective processes for APIs, starting materials, and key intermediates for many critical medicines.

In support of M4ALL’s mission, M4ALL will host a webinar to introduce our research on “An Efficient Synthesis (R)-3-aminobutanol in Route to Dolutegravir” on November 18, 2019.  Participants may register for the webinar through the registration website until the date of the webinar.  The purpose of this webinar is to provide technical information on M4ALL’s one-step protocol for the preparation of (R)-3-aminobutan-2-ol from commercially available D-β-homoalanine. Using materials originating from the chiral pool, asymmetric methodologies and chiral resolution procedures are avoided. A simple one-step process leverages low-cost commodity materials and results in a 70% cost reduction of the aminoalcohol and a 19% cost reduction in the final API. M4ALL have previously reported a continuous process for producing the pyridone intermediate and we now disclose a low-cost process to access the optically active aminoalcohol. Our objective is to encourage interested parties to adopt our improved technologies.

M4ALL will release a process development report in November 2019 upon request.

Market Summary: DTG is becoming a first-line therapy for HIV patients in more than 50-low to middle-income countries. The market for dolutegravir API is conservatively projected to reach 250 MT by 2022.

Administrative: All administrative and technical questions should be directed to m4all@vcu.edu. Please refer to the notice number (M4ALL-DTG-2019-2) in all correspondences. This announcement is not a request for proposals. M4ALL will not provide reimbursement for costs incurred in responding to this notice. Respondents are advised that M4ALL will respond within 48 hours.