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Production, supply & technical support of Synhydrid®
Chematek SpAChematek has been the leading name in global fine chemical since its foundation in 1980.Currently the company has several offices in strategic locations all over the world.
The first Synhydrid batch was synthesized in1971. In spring 2005, the work onconstruction of a modern, large and saferSYNHYDRID® production plant wascommenced at Lucebni in Czech Republic. Bythe end of 2006 the production plant withstate of the art technology and nameplatecapacity of 1200 Mt/year was fullyoperational. In July 2017 capacity has beenfurtherly increased to 1800 Mt/year.
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What is Synhydrid®Sodium bis(2-methoxyethoxy)aluminumhydride
• CAS No. 22722-98-1• Also generically known as SDMA, Red-Al• 70% solution in toluene• Active species:
• Organometallic reducing agent• Well known and fully commercialised, well documented uses and handling on
large scale (ref Chematek – earlier presentation – available on request with full supporting data on handling, packaging, safety etc)
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What is Synhydrid® • Generically known as SDMA (Acronym for the full chemical name)• SDMA is Branded “SYNHYDRID®”• It is probably best known for a number of classic transformations, and
for its ability to replace the more reactive and hazardous Lithium Aluminium Hydride (LAH)
• Historically, when Innovators developed API’s they tended to use LAH as the standard reducing agent for certain types of reaction, and it was not until full commercialisation, and often, generic manufacturers in different geographical locations found LAH extremely hazardous – (with numerous fires) – that an alternative cost effective and safer solution was sought…….
• It is well known and is used in API synthesis in many drugs, in F&F and Agchem AI’s as well as some performance based products
Synhydrid®
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Key Reactions
From To
Amide Amine
Ketone Alcohol
Anhydride Alcohols
Imine Amine
Nitrile Amine
Acid Chloride Alcohol
Acid Alcohol
Ester Alcohol
ChematekSynhydrid®
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Additionally:
Epoxide opening to Alcohol
Wikepedia - SDMA• SDMA is a safer substitute for LAH and related hydrides. • SDMA exhibits similar reducing effects, but does not have the
inconvenient pyrophoric nature, short shelf-life, toxicity or limited solubility of LAH.
• SDMA upon contact with air and moisture, reacts exothermically but does not ignite, and tolerates temperatures up to 200 °C.
• SDMA has unlimited shelf life Under dry conditions. • SDMA is soluble in aromatic solvents, whereas LAH is only soluble in
ethers.• SDMA solution, greater than 70 wt.% concentration in toluene is
commercially available,
• It is now well known and is used in API synthesis in many drugs, also in F&F and Agchem AI’s as well as some performance based products and is more economically effective than LAH
SDMA = Synhydrid®
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Key current commercial uses
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USE Innovator Therapy USE Innovator Therapy
Aglometine Servier Antidepressant Emtricitabine Emory - Gilead HIV
Alfentanil hydrochloride Piramal Enterprises Anesthesia Eprosartan GSK Antihypertension
Aliskiren Novartis Antihypertension Fesoterodine Schwartz Bladder control
Ambrox Firmenich Perfume Fingolimod hydrochloride Mitsubishi Tanabe Pharma Multiple sclerosis
Amphotericin B Bristol-Myers Squibb Infection, fungal Fluoxetine Lilly Antidepressant
Asenapine maleate Allergan Schizophrenia Fluvastatin Novartis Anticholesterol
Atomoxine Lilly ADHDGadoxetic acid disodium
saltBayer
Imaging, magnetic resonance
Buprenorphine Reckitt Benkiser Opiod dependancy Galantamine Bonnie Davis Alzheimers
Capecitabine Hoffmann La Roche Anticancer Gemcitabine Lilly Anticancer
Ceftobiprole medocaril Basilea PharmaceuticaPneumonia, Hospital-
acquiredIsavuconazonium sulfate
Astellas PharmaBasilea Pharmaceutica
Antifungal
Cinacalcet Amgen hyperparathyroidism Ivabradine hydrochloride Servier Angina pectoris
Citalopram Lundbeck Antidpressant Lamivudine GSK HIV
Cyproconazole Syngenta Fungicide Lanopepden GSK Antibacterial
Dapozetine Liily Premature ejaculation Latanoprost Pfizer Antiglaucoma
Darunavir Janssen Infection, HIV Levamisole hydrochlorideJanssen
Kyowa Hakko KirinCancer
Dextromethorphan Hoffmann La Roche Antitussive Lopinavir Abbott HIV
Desvenlafaxine succinate Pfizer Depression Lurasidone hydrochloride Sunovion Schizophrenia
Donepezil Easai Alzheimers Mecamyline Merck Antihypertension
Dorzolomide Merck Antiglaucoma Menthol Takasago F&F
Eletriptan Pfizer Migraine Mericitabine Roche HCV
Darunavir Janssen Infection, HIV Mirtazipine Akzo Antidepressant
Key current commercial uses
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USE Innovator Therapy USE Innovator Therapy
Mosapride citrateSumitomo Dainippon
PharmaGastritis Sorbyl Acetate Suterra Pheromone
Moxifloxacin Bayer Antibacterial Sofosbuvir Gilead (Originator) Anti-Hepatitis C Virus
Naltrexone hydrochloride Bristol-Myers Squibb Opioid dependency SQ109 Sequella Inc Antibacterial
Nebivolol Janssen Antihypertension Sufentanil Janssen Analgesic
Nefopam hydrochloride Biocodex Pain Tapentadol Grünenthal Analgesic
Olanzipine Lilly Antischizophrenia Ticagrelor AstraZeneca Thrombosis, arterial
Orteronel Takeda Prostate Cancer Tofacitinib citrate Pfizer (Originator) Rheumatoid arthritis
Oxycodone Purdue Analgesic TolvaptanOtsuka Pharmaceutical
(Originator)Hyponatremia
Paclitaxel BMS Anticancer Trabectedin PharmaMar Cancer
Paroxetine GSK Anti depressant Tolterodine Pharmacia Incontinence
Pentazocine Sanofi (Astellas) Analgesic Trabectadin Univ. Illinois Antitumour
PeramivirGreen Cross
ShionogiInfluenza Treosulfan Medac Cancer
Phenserine Axonyx Alzheimers Venlafaxine Wyeth Antidepressant
Pitavastatin calciumKowa
Nissan ChemicalHypercholesterolemia Vernakalant hydrochloride Cardiome Antiarrhythmic
Reboxitine Farmitalia Antidepressant Vilazodone hydrochloride Allergan Depression
Ritonivir Abbott HIV
Romidepsin National Cancer Inst Anticancer
Salbutamol Allen & Hanbury Bronchodilator
Other reducing agents….
• SBH/LBH• SBH - Sodium Borohydride/LBH - Lithium Borohydride
• SBH/LBH with Lewis acids • DIBAL
• Diisobutyl Aluminium Hydride
• TBLAH• Tri-tButoxy Lithium Aluminium Hydride
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Other reducing agents….• SBH/LBH
• Generally these are used in protic solvents, usually methanol, ethanol or with aqueous based systems.
• In this case there are probably other reasons to use these such as getting the product isolated easily from salts, or water soluble impurities.
• Synhydrid® cannot be used in protic or aqueous based systems for obvious reasons……it will react itself with the media.
• In the event that SBH/LBH is used in say, a glyme which is aprotic, then a direct switch is feasible.
• The cost difference is around 20-30% - but as the cost of Lithium is rising, certainly in LBH this has a high impact on cost :
• LiBH4 mwt = 21.78, Li = 6.94 – therefore is 32% of the cost, and it is obviously not part of Synhydrid®.
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• SBH/LBH with Aluminium Trichloride• Over recent years, people have used Aluminium Chloride to strengthen
the activity of SBH (or LBH) in particular• There have been numerous fires reported! – consider what is happening
3 NaBH4 + 4 AlCl3 → 4 AlH3 + 3 NaBCl43 LiBH4 + 4 AlCl3 → 4 AlH3 + 3 LiBCl4
Also, Alane reacts with water to evolve copious amounts of hydrogen:
2AlH3 + 6 H2O → 2 Al(OH)3 + 3 H2
1. Alane is generated in-situ. 2. Alane decomposes violently with air and moisture.
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Other reducing agents….
• SBH/LBH with Boron Trifluoride/Trichloride• Even more recently, people have used Boron Trihalides to strengthen
the activity of SBH (or LBH) in particular by forming diborane in-situ• Again there have been numerous fires reported! – consider what is
happening3 NaBH4 + 4 BF3 → 2 B2H6 + 3 NaBF4
3 LiBH4 + 4 BCl3 → 2 B2H6 + 3 LiBCl4
Diborane also reacts with water to evolve copious amounts of hydrogen:
B2H6 + 6 H2O → 2 B(OH)3 + 6 H2
1. Diborane is generated. 2. This is a very flammable toxic gas. 3. It is a flame accelerator4. It Auto-ignition temperature is 38C (explosive limits 0.8 – 88%)5. It can be used as rocket fuel……… 12
Other reducing agents….
• DIBAL - Diisobutyl Aluminium Hydride
• DIBAL has become a commercial item in the last decade or so.• Although DIBAL can be purchased commercially as a colourless liquid, it
is more commonly purchased and dispensed as a solution in an organic solvent such as toluene or hexane.
• DIBAL is normally used because of its selectivity• DIBAL can convert esters and nitriles to aldehydes (vs LAH which
reduces to alcohols). • DIBAL reduces α-β unsaturated esters to the corresponding allylic
alcohol• DIBAL is difficult to handle in flammable, low flash point solvents, reacts
explosively with water and can cause fires. 13
Other reducing agents….
• TBLAH - Tri-tButoxy Lithium Aluminium Hydride
• Even more recently, the introduction of TBLAH, another selective reducing reagent has expanded options for the organic chemist.
• However, although comparable to DIBAL and Synhydrid®, it is just as difficult to handle as DIBAL, and nowhere near as easy to use as Synhydrid®.
• TBLAH is highly flammable.• TBLAH is highly reactive with air.• Again, any moisture, oxygen etc. will decompose it and form hydrogen gas.
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Other reducing agents….
Synhydrid®
• For over 50 years, SYNHYDRID® has been used around the world.• Its inherent stability, reactivity and ease of handling – even in area’s of high
humidity, make it the reagent of choice for organometallic reductions.• It is stable under normal conditions (provided it is made correctly!).• It does not form explosive mixtures upon treatment with water or air.• It is selective, and is comparable to DIBAL and TBLAH and is currently used in
many cases, to replace LAH and SBH/LBH (with added lewis acid), DIBAL and TBLAH.
• Many people are aware of the comparison with LAH and SBH, but few know the ability for SYNHYDRID® to be used to replace DIBAL and TBLAH. 15
Name LAH Synhydrid® DiBAL TBLAH
Structure
H available Four Two One One
Conc. 95% 70% 25% 26%
H (g/kg) 100.1 6.89 1.76 1.02
Comparison of reductants
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Comparison of reductantsMoles (theoretical)
Synhydrid® LAH DiBAl TBLAHAcid chloride to alcohol 1 0.5 2 2
Acid chloride to aldehyde 0.5 0.25 1 1Acid to aldehyde 0.5 0.25 1 1
Aldehyde to alcohol 0.5 0.25 1 1
Alkene to alkane 2 1 4 4Alkyne to alkene 0.5 0.25 1 1
Amide to amine 1 0.5 2 2
Amino acid to amino alcohol 1 0.5 2 2Anhydride to diol 2 1 4 4
Carboxylic acid to alcohol 1 0.5 2 2Carboxylic acid to aldehyde 0.5 0.25 1 1
Ester to alcohol 1 0.5 2 2Ester to aldehyde 0.5 0.25 1 1
Imine to amine 0.5 0.25 1 1
Ketone to alcohol 0.5 0.25 1 1
Lactone to diol 1 0.5 2 2Lactone to lactol 0.5 0.25 1 1Nitrile to alcohol 1 0.5 2 2
Nitrile to aldehyde 0.5 0.25 1 1Nitrile to amine 1 0.5 2 2 17
Volume efficacy of Synhydrid®
• Consider the actual strength of solution of SYNHYDRID® vs competitive selective reducing agents – as SYNHYDRID® is ~3 times more soluble in solvents, then the volume utilisation in your reactor is much better
• So the reduction using SYNHYDRID® can be done more efficiently with bigger batch sizes and fewer batches – reducing overall labour and utility cost.
MWT % w/w Solution Density mls/mol
Synhydrid® 202.16 70 1.122 257
DIBAL 142.22 25 0.798 713
TBLAH 254.26 26 0.9 1087
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Comparison of reductant volumeGrams reductant per mole substrate
Synhydrid® LAH DiBAl TBLAHAcid chloride to alcohol 289 20 1,136 1,954
Acid chloride to aldehyde 144 10 568 977Acid to aldehyde 144 10 568 977
Aldehyde to alcohol 144 10 568 977
Alkene to alkane 578 40 2,272 3,908Alkyne to alkene 144 10 568 977
Amide to amine 289 20 1,136 1,954
Amino acid to amino alcohol 289 20 1,136 1,954Anhydride to diol 578 40 2,272 3,908
Carboxylic acid to alcohol 289 20 1,136 1,954Carboxylic acid to aldehyde 144 10 568 977
Ester to alcohol 289 20 1,136 1,954Ester to aldehyde 144 10 568 977
Imine to amine 144 10 568 977
Ketone to alcohol 144 10 568 977
Lactone to diol 289 20 1,136 1,954Lactone to lactol 144 10 568 977Nitrile to alcohol 289 20 1,136 1,954
Nitrile to aldehyde 144 10 568 977Nitrile to amine 289 20 1,136 1,954 19
• Cost of SYNHYDRID® is significantly lower than DIBAL, TBLAH and LAH
• Volume of SYNHYDRID®is much lower than DIBAL and TBLAH – which means better throughput and lower cost…
• Hazards of LAH, DIBAL and TBLAH make SYNHYDRID® the preferred choice.
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Comparison summary
• Ketone reduction e.g. in Salmeterol synthesis
• Other ketone reduction example e.g. Flavours & Fragrances synthesis
Classic Reductions of Synhydrid®
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SDMACH3
OCH3
CH3
CH3
OHCH3
CH3
Classic Reductions of Synhydrid®
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• Aldehyde reduction e.g. in Bosentan synthesis
• Nitroso reduction e.g. in Clopamide synthesis
• Acid reduction e.g. in Mirtazapine synthesis
Classic Reductions of Synhydrid®
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• Ester reduction e.g. in Tolterodine synthesis
• Amide reduction e.g. in Venlafaxine synthesis
• Lactone FULL reduction e.g. in Ambroxan synthesis
Classic Reductions of Synhydrid®
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SDMA
Alpha-Ambrinol
SDMAX=Cl, Br
• Alpha-Ambrinol synthesis: Halohydrin reduction / Epoxide opening
• Nitrile reduction e.g. in Heterocyclic aldehyde or amine formation
• Sometimes multiple reductions e.g. in Galantamine synthesis
Classic Reductions of Synhydrid®
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X = O, S
• Bis Imide FULL reduction in Boceprevir synthesis:
Classic Reductions of Synhydrid®
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• Bis Imide FULL reduction in Moxifloxacin synthesis:
SELECTIVITY & Synhydrid®
• For over 50 years, SYNHYDRID® has been used around the world, often replacing LAH in chemical synthesis and commercial API’s etc
• Its inherent stability, reactivity and ease of handling – even in area’s of high humidity, make it the reagent of choice for organometallic reductions.
• It is well known for reductions such as those discussed earlier, Ester to alcohol, amide to amine, nitrile to amine etc.
• We now wish to expand the knowledge and discuss selective reductions that SYNHYDRID® can be used for based on modification of the ligand to replace reagents such as DIBAL and TBLAH.
HOW WE MODIFY Synhydrid® & WHY
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Donepezil• This is one of the first examples of an API with a reduction using “softening” of
SYNHYDRID®, (reducing the power), by replacing one of the two available hydrides by an amine
• A conversion of an ester to an aldehyde.
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Methyl myristate -> tetradecanal
• DiBAL is well known for partial reductions, e.g. conversion of esters to aldehydes
• Temperatures are generally very low• Handling of DiBAL has its issues• Yields are often far from satisfactory (44-88%)• Consider US 4983746:
• We have shown that modified SYNHYDRID® will complete the same reduction as DiBAL in higher yields, less extreme temperatures, less hazardous conditions and more cost effectively.
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Methyl myristate -> tetradecanal• How?• Add the amine to reduce the activity of SYNHYDRID®, use 1 meq/mole
Synhydrid®• Inverse addition• 20°C
• Yields are ~90% +
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Comparison Example: SDMA vs TBLAH vs DIBAL in Sofosbuvir synthesis
Lactone-to-Lactol reduction:
Reducing Agent Addition Solvent Temperature Time Product Yield
SDMA* = SDMA/TFE
Reverse DCM -10°C 1 h 76 %
TBLAH Reverse THF -10°C -15°C 3 h 63 %
DIBAL Reverse THF -78°C 6 h Poor conversion
DIBAL Reverse THF -20°C 0.5 h Degradation:lactone opening and debenzoylation
SDMA*
What does this mean?
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• This opens up a whole new option for partial reduction• Better yields• Less extreme temperatures (-20C to +20C) vs -78C for DiBAL• Safer manual handling – no fires! • More cost effective• Better throughput• This means that a whole new list of targets become accessible with greater
ease and less cost!• The following slide identifies these API’s • Those highlighted in green are known to be reduced with SYNHYDRID® and
literature precedents are in the public domain
API’s with partial reductionsCalcifediol Sanofi Launched
Morphine sulfate Astra Zeneca Launched 1909
Travoprost Generic Launched 1963
1,25-Dihydroxyvitamin-D3 Launched 1978
Alprostadil Vivus Launched 1979
Vigabatrin Sanofi Launched 1989
Galantamine hydrobromide Takeda Launched 1995
Gemcitabine hydrochloride Launched 1995
Latanoprost Pfizer Launched 1996
Donepezil Eisai Launched 1997
Nebivolol Launched 1997
Simvastatin MSD Launched 1998
Desogestrel Merck Launched 1999
Bimatoprost Allergan Launched 2001
Ezetimibe Merck Launched 2002
Pitavastatin calcium Daiichi Sankyo, Recordati Launched 2003
Cinacalcet hydrochloride Amgen Launched 2004
Duloxetine hydrochloride Lilly Launched 2004
Clofarabine Genzyme Launched 2005
Romidepsin Celgene Launched 2006
Darunavir Janssen Launched 2006
Fesoterodine fumarate Pfizer Launched 2008
Lacosamide UCB Launched 2008
Asenapine maleate MSD Launched 2009
Saxagliptin BMS Launched 2009
Tapentadol hydrochloride Gruenenthal Launched 2009
Lurasidone hydrochloride Sunovion Launched 2010
Eribulin mesilate Eisai Launched 2010
Telaprevir Vertex Launched 2011
Fidaxomicin Merck Launched 2011
Ticagrelor Astra Zeneca Launched 2011
• The disadvantages of LAH are well known• Handling is extremely difficult due to its pyrophoric nature – there are many examples
in the public domain – both small:
• A researcher at X was seriously injured when reducing a substrate using lithium aluminium hydride (LAH) in tetrahydrofuran (THF). Shortly thereafter, at least two other accidents involving procedures using LAH and THF have been documented. Due to the inherent hazards of LAH and THF, researchers must thoroughly plan out experimental protocols and incorporate safety measure to mitigate the hazards of this procedure. We have consulted with an outside expert in these issues, and he has made a number of important safety recommendations for this procedure.
• And large
• LAH is often frequently used as a 1 Molar solution in THF
Why Synhydrid® vs LAH?
35
• Safety issues of LAH have been highlighted.
• SDMA, being more stable than LAH, can be more effective in terms of equivalents needed: often large excess of LAH is added to push the reaction as LAH is partially quenched over time.
• The solvent of choice is often important:
- LAH is often refluxed in THF (Boiling Point = 66°C) or Diethyl Ether (Boiling Point =34°C).
- SDMA reactions can be heated or refluxed also in Toluene (Boiling Point = 110°C). Toluene can be separated and recovered vs THF is water miscible.
This gives more flexibility on applicable temperature range, and together with higher solubility of SDMA in organic solvents, easier industrialization.
• SDMA reactions are often suitable to less extreme cooling (I.E. -78°C cooling that is often used for LAH).
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Why Synhydrid® vs LAH?
• The ease of handling has been already pointed out.• The safety of SDMA compared to organometallic reducing agents has been highlighted.• The selectivity of the reactions has also been discussed.• Put all that aside (NOT THAT YOU SHOULD).• Compare volume efficacy and cost efficacy of the simplest reactions.
Why Synhydrid® vs DIBAL/TBLAH?
37
Why Synhydrid® vs others?
Note – assumes LAH is used in 1M solution rather than as a solid for obvious reasons!
38
SDMA* = SDMA modified so as to be partially quenched or «softened»:
As we have already seen, SDMA can be partially quenched, so as to perform partial reductions:
Modified Synhydrid®
42
SDMA*= SDMA partially quenched or «softened»
45
Example: Nitrile reduction to Alchoolvia partial reduction to Aldehyde .
CH3
N
CH3
OH
DIBAL
SDMA*CH3
OH
DIBAL
SDMA
1)
2) H2OCH3
OH
DIBAL1)
2) H2O
CH3
H
O
46
DIBAL
SDMA*
CH3
N
Example: Macrocyclic Lactones as fragrances: Nitrile to Aldehyde partial reduction.
SDMA*= SDMA partially quenched or «softened»
N
CH3
O
CH3
H
SDMA*
DIBAL
Ingredient in fragranceformulation.
1)
2) H2O
SDMA*= SDMA partially quenched or «softened»
47
Example: Cyclolalkane Aldehydes from Nitriles.
DIBAL1)
2) H2O
SDMA*
Ox Cond.
48
Example: P-Menthane Aldeydes from Nitriles.
SDMA*= SDMA partially quenched or «softened»
SDMA*= SDMA partially quenched or «softened»
49
Example: partial reduction of Lactone to Lactol: Latanoprost .
DIBAL
SDMA*
SDMA*= SDMA partially quenched or «softened»
50
Example: partial reduction of Lactone to Lactol: Simvastatin.
DIBAL
SDMA*
SDMA*= SDMA partially quenched or «softened»
51
Example: partial reduction of Lactone to Lactol: Niraparib.
DIBAL
SDMA*
SDMA*= SDMA partially quenched or «softened»
52
Example: partial reduction of Lactone to Lactol: Rolapitant.
LAH
SDMA*
KHMDS
1)
2)
53
Lactol-derived fragrances
SDMADIBAL
SDMA*
SDMA* = SDMA modified so as to be partially quenched or «softened»:
Example: Lactol-structured fragrances: Lactone-to-Lactol reduction.
SDMA*= SDMA partially quenched or «softened»
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Example: partial reduction of Ester to Aldehyde:Sunitinib Malate.
DIBAL
SDMA*
O
O
O
CH3
OH
H
OSDMA*
Citronella-like fragranceSDMA*= SDMA partially quenched or «softened»
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Oxidation
Example: Citronella-like aldehyde fragrance synthesis by partial reduction of Ester to Aldehyde.
SDMA
LAH
O
OCH3
CH3
56
SDMA*
DIBALH
OCH3
N
CH3
1) NH2OH
2) NaOH
SDMA* = SDMA modified so as to be partially quenched or «softened».
Example: Cyclopentyl-Alkyl-Nitriles by reduction of Ester to Aldehyde.
CH3
CH3
CH2
CH2
H
O
CH3
CH3
CH2
CH2
OHCH3
CH3
CH2
CH2
O
O
R
57
SDMA
LAH
SDMA*
Terpenic aldehyde fragrance
Ooxidation
SDMA* = SDMA modified so as to be partiallyquenched or «softened»:
Example: Terpene flavorantsby reduction of Ester to Aldehyde.
58
SDMA
LAH
CH3CH3
CH2 CH3
OH
O
CH3CH3
CH2 CH3
O
H
CH3CH3
CH2 CH3
OH
SDMA*
DIBAL
SDMA* = SDMA modified so as to be partially quenched or «softened»:
Example: Lavandulic acid derivatives by reduction of Carboxylic Acid to Aldehyde and Alcohol.
O
O
O
CH3
CH3
OH
CH3
O
O
CH3
OH
CH3
HSDMA*
DIBAL
SDMA* = SDMA modified so as to be partially quenched or «softened»:
59
Example: Pyran Aldehydes from Esters
SDMA*
DIBAL
O
O
CH3CH3
O
CH3 H
CH3 NH
O
CH3
CH3
SDMA* = SDMA modified so as to be partially quenched or «softened»:
60
Example: Spilanthol synthesis: Ester to Aldehyde.
61
Example of Diastereoselective Synthesis:
Sirolimus synthesis: Lactone to Lactol.
DIBAL
SDMA*
1)
2) TBDMSCl, Imidazole
SDMA*= SDMA partially quenched or «softened»
Safety , Selectivity , Cost !
We’re here to helpDr. Riccardo LIBORICommercial DirectorCHEMATEKT. +33 4 90 03 27 84M. +33 6 84 93 99 02Fax. : +33 9 70 60 04 31libori@chematek.biz
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