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ORGANIC SPECTROSCOPY

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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FDA approves new treatment Galafold (migalastat) for a rare genetic disorder, Fabry disease


FDA approves new treatment for a rare genetic disorder, Fabry disease

The U.S. Food and Drug Administration today approved Galafold (migalastat), the first oral medication for the treatment of adults with Fabry disease. The drug is indicated for adults with Fabry disease who have a genetic mutation determined to be responsive (“amenable”) to treatment with Galafold based on laboratory data. Fabry disease is a rare and serious genetic disease that results from buildup of a type of fat called globotriaosylceramide (GL-3) in blood vessels, the kidneys, the heart, the nerves and other organs.

August 10, 2018

Release

The U.S. Food and Drug Administration today approved Galafold (migalastat), the first oral medication for the treatment of adults with Fabry disease. The drug is indicated for adults with Fabry disease who have a genetic mutation determined to be responsive (“amenable”) to treatment with Galafold based on laboratory data. Fabry disease is a rare and serious genetic disease that results from buildup of a type of fat called globotriaosylceramide (GL-3) in blood vessels, the kidneys, the heart, the nerves and other organs.

“Thus far, treatment of Fabry disease has involved replacing the missing enzyme that causes the particular type of fat buildup in this disease. Galafold differs from enzyme replacement in that it increases the activity of the body’s deficient enzyme,” said Julie Beitz, M.D., director of the Office of Drug Evaluation III in FDA’s Center for Drug Evaluation and Research.

Fabry disease is an inherited disorder caused by mutations (alterations) in the alpha-galactosidase A (GLA) gene located on the X-chromosome. Fabry disease is rare and affects both males and females. It is estimated that classic Fabry disease (the most severe type) affects approximately one in 40,000 males. The later-onset type is more frequent, and in some populations, may occur in one in 1,500 to 4,000 males. Patients with Fabry disease develop slowly progressive kidney disease, cardiac hypertrophy (enlargement of the heart), arrhythmias (abnormal heart rhythm), stroke and early death.

The efficacy of Galafold was demonstrated in a six-month, placebo-controlled clinical trial in 45 adults with Fabry disease. In this trial, patients treated with Galafold over six months had a greater reduction in globotriaosylceramide (GL-3) in blood vessels of the kidneys (as measured in kidney biopsy samples) as compared to patients on placebo.The safety of Galafold was studied in four clinical trials which included a total of 139 patients with Fabry disease.

The most common adverse drug reactions in patients taking Galafold in clinical trials were headache, nasal and throat irritation (nasopharyngitis), urinary tract infection, nausea, and fever (pyrexia).

Galafold was approved using the Accelerated Approval pathway, under which the FDA may approve drugs for serious conditions where there is an unmet medical need and where a drug is shown to have certain effects that are reasonably likely to predict a clinical benefit to patients. A further study is required to verify and describe the clinical benefits of Galafold, and the sponsor will be conducting a confirmatory clinical trial of Galafold in adults with Fabry disease.

Galafold  was granted Priority Review designation, under which the FDA’s goal is to take action on an application within six months of application filing where the agency determines that the drug, if approved, would provide a significant improvement in treating, diagnosing or preventing a serious condition over available therapies. Galafold also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.
The FDA granted approval of Galafold to Amicus Therapeutics U.S., Inc.

///////////////fda 2018, Galafold, migalastat, Fabry disease, Amicus Therapeutics

With Persistence And Phase 3 Win, Amicus Nears First Drug Approval …….Migalastat


Migalastat hydrochloride

CAS Number: 75172-81-5 hydrochloride

CAS BASE….108147-54-2

ABS ROT = (+)

  +53.0 °
Conc: 1 g/100mL; Solv: water ;  589.3 nm; Temp: 24 °C

IN Van den Nieuwendijk, Adrianus M. C. H.; Organic Letters 2010, 12(17), 3957-3959 

3,4,5-Piperidinetriol,2-(hydroxymethyl)-, hydrochloride (1:1), (2R,3S,4R,5S)-

Molecular Structure:

Molecular Structure of 75172-81-5 (3,4,5-Piperidinetriol,2-(hydroxymethyl)-, hydrochloride (1:1), (2R,3S,4R,5S)-)

Formula: C6H14ClNO4

Molecular Weight:199.63

Synonyms:  3,4,5-Piperidinetriol,2-(hydroxymethyl)-, hydrochloride, (2R,3S,4R,5S)- (9CI);

3,4,5-Piperidinetriol,2-(hydroxymethyl)-, hydrochloride, [2R-(2a,3a,4a,5b)]-;

Migalastat hydrochloride;Galactostatin hydrochloride;

(2S,3R,4S,5S)-2-(hydroxymethyl)piperidine-3,4,5-triol hydrochloride;

  • 1-Deoxygalactonojirimycin
  • 1-Deoxygalactostatin
  • Amigal
  • DDIG
  • Migalastat
  • UNII-C4XNY919FW

Melting Point:160 °C-162…….http://www.google.com/patents/DE3906463A1?cl=de

Boiling Point:382.7 °C at 760 mmHg

Flash Point:185.2 °C

Amicus Therapeutics, Inc. innovator

Aug 2014

http://www.xconomy.com/new-york/2014/08/20/with-persistence-and-phase-3-win-amicus-nears-first-drug-approval/?utm_source=rss&utm_medium=rss&utm_campaign=with-persistence-and-phase-3-win-amicus-nears-first-drug-approval

Amicus Therapeutics was on the ropes in late 2012 when its pill for a rare condition called Fabry Disease108147-54-2 failed a late-stage trial. It had already put seven years of work into the drug, and the setback added even more development time and uncertainty to the mix. But the Cranbury, NJ-based company kept plugging away, and now it looks like all the effort could lead to its first approved drug.

Amicus (NASDAQ: FOLD) is reporting today that the Fabry drug, migalastat, succeeded in the second of two late-stage trials. It hit two main goals that essentially measured its ability to slow the decline of Fabry patients’ kidney function comparably to enzyme-replacement therapy (ERT)—the standard of care for the often-fatal disorder.

Amicus believes the results, along with those from an earlier Phase 3 trial comparing migalastat to a placebo, are good enough to ask regulators in the U.S. and Europe for market approval.

“These are the good days to be a CEO,” says Amicus CEO John Crowley (pictured above). “It’s great when a plan comes together and data cooperates.”

Crowley says Amicus will seek approval of migalastat first in Europe and is already in talks with regulators there. In the next few months, Amicus will begin talking with the FDA about a path for approval in the U.S. as well.

 

 

End feb 2013

About Amicus Therapeutics

Amicus Therapeutics  is a biopharmaceutical company at the forefront of therapies for rare and orphan diseases. The Company is developing orally-administered, small molecule drugs called pharmacological chaperones, a novel, first-in-class approach to treating a broad range of human genetic diseases. Amicus’ late-stage programs for lysosomal storage disorders include migalastat HCl monotherapy in Phase 3 for Fabry disease; migalastat HCl co-administered with enzyme replacement therapy (ERT) in Phase 2 for Fabry disease; and AT2220 co-administered with ERT in Phase 2 for Pompe disease.

About Migalastat HCl

Amicus in collaboration with GlaxoSmithKline (GSK) is developing the investigational pharmacological chaperone migalastat HCl for the treatment of Fabry disease. Amicus has commercial rights to all Fabry products in the United States and GSK has commercial rights to all of these products in the rest of world.

As a monotherapy, migalastat HCl is designed to bind to and stabilize, or “chaperone” a patient’s own alpha-galactosidase A (alpha-Gal A) enzyme in patients with genetic mutations that are amenable to this chaperone in a cell-based assay. Migalastat HCl monotherapy is in Phase 3 development (Study 011 and Study 012) for Fabry patients with genetic mutations that are amenable to this chaperone monotherapy in a cell-based assay. Study 011 is a placebo-controlled study intended primarily to support U.S. registration, and Study 012 compares migalastat HCl to ERT to primarily support global registration.

For patients currently receiving ERT for Fabry disease, migalastat HCl in combination with ERT may improve ERT outcomes by keeping the infused alpha-Gal A enzyme in its properly folded and active form thereby allowing more active enzyme to reach tissues.2Migalastat HCl co-administered with ERT is in Phase 2 (Study 013) and migalastat HCl co-formulated with JCR Pharmaceutical Co. Ltd’s proprietary investigational ERT (JR-051, recombinant human alpha-Gal A enzyme) is in preclinical development.

About Fabry Disease

Fabry disease is an inherited lysosomal storage disorder caused by deficiency of an enzyme called alpha-galactosidase A (alpha-Gal A). The role of alpha-Gal A within the body is to break down specific lipids in lysosomes, including globotriaosylceramide (GL-3, also known as Gb3). Lipids that can be degraded by the action of α-Gal are called “substrates” of the enzyme. Reduced or absent levels of alpha-Gal A activity leads to the accumulation of GL-3 in the affected tissues, including the kidneys, heart, central nervous system, and skin. This accumulation of GL-3 is believed to cause the various symptoms of Fabry disease, including pain, kidney failure, and increased risk of heart attack and stroke.

It is currently estimated that Fabry disease affects approximately 5,000 to 10,000 people worldwide. However, several literature reports suggest that Fabry disease may be significantly under diagnosed, and the prevalence of the disease may be much higher.

1. Bichet, et al., A Phase 2a Study to Investigate the Effect of a Single Dose of Migalastat HCl, a Pharmacological Chaperone, on Agalsidase Activity in Subjects with Fabry Disease, LDN WORLD 2012

2. Benjamin, et al.Molecular Therapy: April 2012, Vol. 20, No. 4, pp. 717–726.

http://clinicaltrials.gov/show/NCT01458119

http://www.docstoc.com/docs/129812511/migalastat-hcl

 

Migalastat hydrochloride is a pharmacological chaperone in phase III development at Amicus Pharmaceuticals for the oral treatment of Fabry’s disease. Fabry’s disease occurs as the result of an inherited genetic mutation that results in the production of a misfolded alpha galactosidase A (alpha-GAL) enzyme, which is responsible for breaking down globotriaosylceramide (GL-3) in the lysosome. Migalastat acts by selectively binding to the misfolded alpha-GAL, increasing its stability and promoting proper folding, processing and trafficking of the enzyme from the endoplasmic reticulum to the lysosome.

In February 2004, migalastat hydrochloride was granted orphan drug designation by the FDA for the treatment of Fabry’s disease.

The EMEA assigned orphan drug designation for the compound in 2006 for the treatment of the same indication. In 2007, the compound was licensed to Shire Pharmaceuticals by Amicus Therapeutics worldwide, with the exception of the U.S., for the treatment of Fabry’s disease.

In 2009, this license agreement was terminated. In 2010, the compound was licensed by Amicus Therapeutics to GlaxoSmithKline on a worldwide basis to develop, manufacture and commercialize migalastat hydrochloride as a treatment for Fabry’s disease, but the license agreement terminated in 2013.

 

Chemical Name: DEOXYGALACTONOJIRIMYCIN, HYDROCHLORIDE
Synonyms: DGJ;Amigal;Unii-cly7m0xd20;GALACTOSTATIN HCL;DGJ, HYDROCHLORIDE;Migalastat hydrochloride;Galactostatin hydrochloride;DEOXYGALACTONOJIRIMYCIN HCL;1-DEOXYGALACTONOJIRIMYCIN HCL;1,5-dideoxy-1,5-imino-d-galactitol

DEOXYGALACTONOJIRIMYCIN, HYDROCHLORIDE Structure

 

………………………..

Links

http://www.google.co.in/patents/WO1999062517A1?cl=en

Example 1

A series of plant alkaloids (Scheme 1, ref. 9) were used for both in vitro inhibition and intracellular enhancement studies of α-Gal A activity. The results of inhibition experiments are shown in Fig. 1 A.

 

f^

 

Among the tested compounds, 1-deoxy-galactonojirimycin (DGJ, 5) known as a powerful competitive inhibitor for α-Gal A, showed the highest inhibitory activity with IC50 at 4.7 nM. α-3,4-Di-epi-homonojirimycin (3) was an effective inhibitor with IC50 at 2.9 μM. Other compounds showed moderate inhibitory activity with IC50 ranging from 0.25 mM (6) to 2.6 mM (2). Surprisingly, these compounds also effectively enhanced α-Gal A activity in COS-1 cells transfected with a mutant α-Gal A gene (R301Q), identified from an atypical variant form of Fabry disease with a residual α- Gal A activity at 4% of normal. By culturing the transfected COS-1 cells with these compounds at concentrations cat 3 – 10-fold of IC50 of the inhibitors, α-Gal A activity was enhanced 1.5 – 4-fold (Fig. 1C). The effectiveness of intracellular enhancement paralleled with in vitro inhibitory activity while the compounds were added to the culture medium at lOμM

concentration (Fig. IB).

………………………

Links

WO 2008045015

or  http://www.google.com/patents/EP2027137A1?cl=enhttp://www.google.com/patents/US7973157?cl=en

This invention relates to a process for purification of imino or amino sugars, such as D-1-deoxygalactonojirimycin hydrochloride (DGJ’HCl). This process can be used to produce multi-kilogram amounts of these nitrogen-containing sugars.

Sugars are useful in pharmacology since, in multiple biological processes, they have been found to play a major role in the selective inhibition of various enzymatic functions. One important type of sugars is the glycosidase inhibitors, which are useful in treatment of metabolic disorders. Galactosidases catalyze the hydrolysis of glycosidic linkages and are important in the metabolism of complex carbohydrates. Galactosidase inhibitors, such as D-I- deoxygalactonojirimycin (DGJ), can be used in the treatment of many diseases and conditions, including diabetes (e.g., U.S. Pat. 4,634,765), cancer (e.g., U.S. Pat. 5,250,545), herpes (e.g. , U.S. Pat. 4,957,926), HIV and Fabry Disease (Fan et al, Nat. Med. 1999 5:1, 112-5).

Commonly, sugars are purified through chromatographic separation. This can be done quickly and efficiently for laboratory scale synthesis, however, column chromatography and similar separation techniques become less useful as larger amounts of sugar are purified. The size of the column, amount of solvents and stationary phase (e.g. silica gel) required and time needed for separation each increase with the amount of product purified, making purification from multi-kilogram scale synthesis unrealistic using column chromatography.

Another common purification technique for sugars uses an ion- exchange resin. This technique can be tedious, requiring a tedious pre-treatment of the ion exchange resin. The available ion exchange resins are also not necessarily able to separate the sugars from salts (e.g., NaCl). Acidic resins tend to remove both metal ions found in the crude product and amino- or imino-sugars from the solution and are therefore not useful. Finding a resin that can selectively remove the metal cations and leave amino- or imino-sugars in solution is not trivial. In addition, after purification of a sugar using an ion exchange resin, an additional step of concentrating the diluted aqueous solution is required. This step can cause decomposition of the sugar, which produces contaminants, and reduces the yield.

U.S. Pats. 6,740,780, 6,683,185, 6,653,482, 6,653,480, 6,649,766, 6,605,724, 6,590,121, and 6,462,197 describe a process for the preparation of imino- sugars. These compounds are generally prepared from hydroxyl-protected oxime intermediates by formation of a lactam that is reduced to the hexitol. However, this process has disadvantages for the production on a multi-kg scale with regard to safety, upscaling, handling, and synthesis complexity. For example, several of the disclosed syntheses use flash chromatography for purification or ion-exchange resin treatment, a procedure that is not practicable on larger scale. One particularly useful imino sugar is DGJ. There are several DGJ preparations disclosed in publications, most of which are not suitable for an industrial laboratory on a preparative scale (e.g., >100 g). One such synthesis include a synthesis from D-galactose (Santoyo-Gonzalez, et al, Synlett 1999 593-595; Synthesis 1998 1787-1792), in which the use of chromatography is taught for the purification of the DGJ as well as for the purification of DGJ intermediates. The use of ion exchange resins for the purification of DGJ is also disclosed, but there is no indication of which, if any, resin would be a viable for the purification of DGJ on a preparative scale. The largest scale of DGJ prepared published is 13 g (see Fred-Robert Heiker, Alfred Matthias Schueller, Carbohydrate Research, 1986, 119-129). In this publication, DGJ was isolated by stirring with ion-exchange resin Lewatit MP 400 (OH) and crystallized with ethanol. However, this process cannot be readily scaled to multi- kilogram quantities.

Similarly, other industrial and pharmaceutically useful sugars are commonly purified using chromatography and ion exchange resins that cannot easily be scaled up to the purification of multi-kilogram quantities.

Therefore, there is a need for a process for purifying nitrogen- containing sugars, preferably hexose amino- or imino-sugars that is simple and cost effective for large-scale synthesis

FIG. 1. HPLC of purified DGJ after crystallization. The DGJ is over 99.5% pure.

 

 

FIG. 2A. 1H NMR of DGJ (post HCl extraction and crystallization), from 0 – 15 ppm in DMSO.

FIG. 2B. 1H NMR of DGJ (post HCl extraction and crystallization), from 0 – 5 ppm, in DMSO.

 

FIG. 3 A. 1H NMR of purified DGJ (after recrystallization), from 0 – 15 ppm, in D2O. Note OH moiety has exchanged with OD.

FIG. 3B. 1H NMR of purified DGJ (after recrystallization), from 0 –

4 ppm, in D2O. Note OH moiety has exchanged with OD.

 

FIG. 4. 13C NMR of purified DGJ, (after recrystallization), 45 – 76 ppm.

 

One amino-sugar of particular interest for purification by the method of the current invention is DGJ. DGJ, or D-l-deoxygalactonojirimycin, also described as (2R,3S,4R,5S)-2-hydroxymethyl-3,4,5-trihydroxypiperidine and 1- deoxy-galactostatin, is a noj irimycin (5-amino-5-deoxy-D-galactopyranose) derivative of the form:

Figure imgf000011_0001
 

Example 1: Preparation and Purification of DGJ

A protected crystalline galactofuranoside obtained from the technique described by Santoyo-Gonzalez. 5-azido-5-deoxy-l,2,3,6-tetrapivaloyl-α-D- galactofuranoside (1250 g), was hydrogenated for 1-2 days using methanol (10 L) with palladium on carbon (10%, wet, 44 g) at 50 psi of H2. Sodium methoxide (25% in methanol, 1.25 L) was added and hydrogenation was continued for 1-2 days at 100 psi ofH2. Catalyst was removed by filtration and the reaction was acidified with methanolic hydrogen chloride solution (20%, 1.9 L) and concentrated to give crude mixture of DGJ • HCl and sodium chloride as a solid. The purity of the DGJ was about 70% (w/w assay), with the remaining 30% being mostly sodium chloride.

The solid was washed with tetrahydrofuran (2 x 0.5 L) and ether (I x 0.5 L), and then combined with concentrated hydrochloric acid (3 L). DGJ went into solution, leaving NaCl undissolved. The obtained suspension was filtered to remove sodium chloride; the solid sodium chloride was washed with additional portion of hydrochloric acid (2 x 0.3 L). All hydrochloric acid solution were combined and slowly poured into stirred solution of tetrahydrofuran (60 L) and ether (11.3 L). The precipitate formed while the stirring was continued for 2 hours. The solid crude DGJ* HCl, was filtered and washed with tetrahydrofuran (0.5 L) and ether (2 x 0.5 L). An NMR spectrum is shown in FIGS. 2A-2B.

The solid was dried and recrystallized from water (1.2 mL /g) and ethanol (10 ml/1 ml of water). This recrystallization step may be repeated. This procedure gave white crystalline DGJ* HCl, and was usually obtained in about 70- 75% yield (320 – 345 g). The product of the purification, DGJ-HCl is a white crystalline solid, HPLC >98% (w/w assay) as shown in FIG. 1. FIGS. 3A-3D and FIG. 4 show the NMR spectra of purified DGJ, showing the six sugar carbons.

Example 2: Purification of 1-deoxymannojirimycin 1 -deoxymannojirimycin is made by the method described by Mariano

(J. Org. Chem., 1998, 841-859, see pg. 859, herein incorporated by reference). However, instead of purification by ion-exchange resin as described by Mariano, the 1-deoxymannojirimycin is mixed with concentrated HCl. The suspension is then filtered to remove the salt and the 1-deoxymannojirimycin hydrochloride is precipitated crystallized using solvents known for recrystallization of 1- deoxymannojirimycin (THF for crystallization and then ethanol/water.

Example 3: Purification of (+)-l-deoxynojirimycin

(+)-l-deoxynojirimycin is made by the method Kibayashi et al. (J. Org. Chem., 1987, 3337-3342, see pg. 334I5 herein incorporated by reference). It is synthesized from a piperidine compound (#14) in HCl/MeOH. The reported yield of 90% indicates that the reaction is essentially clean and does not contain other sugar side products. Therefore, the column chromatography used by Kibayashi is for the isolation of the product from non-sugar related impurities. Therefore, instead of purification by silica gel chromatography, the (+)-l-deoxynojirimycin is mixed with concentrated HCl. The suspension is then filtered to remove the salt and the nojirimycin is crystallized using solvents known for recrystallization of nojirimycin.

Example 4: Purification of Nojirimycin

Nojirimycin is made by the method described by Kibayashi et al. (J.

Org. Chem., 1987, 3337-3342, see pg. 3342). However, after evaporating of the mixture at reduced pressure, instead of purification by silica gel chromatography with ammonia-methanol-chloroform as described by Kibayashi, the nojirimycin is mixed with concentrated HCl. The suspension is then filtered to remove the impurities not dissolved in HCl and the nojirimycin is crystallized using solvents known for recrystallization of nojirimycin.

 

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Links

Synthesis of (+)-1-deoxygalactonojirimycin and a related indolizidine

Tetrahedron Lett 1995, 36(5): 653

Amido-alcohol 1 is transformed via aminal 2 into 1-deoxygalactonojirimycin (3) and the structurally related indolizidine 4.

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Links

Synthesis of D-galacto-1-deoxynojirimycin (1,5-dideoxy-1,5-imino-D-galactitol) starting from 1-deoxynojirimycin

Carbohydr Res 1990, 203(2): 314

………………………………..

Synthesis of (+)-1,5-dideoxy-1,5-imino-D-galactitol, a potent alpha-D-galactosidase inhibitor

Carbohydr Res 1987, 167: 305

 

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Links

SEE

Monosaccharides containing nitrogen in the ring, XXXVII. Synthesis of 1,5-didexy-1,5-imino-D-galactitol

Chem Ber 1980, 113(8): 2601

…………………………

Links

Org. Lett., 2010, 12 (17), pp 3957–3959
DOI: 10.1021/ol101556k

http://pubs.acs.org/doi/abs/10.1021/ol101556k

  +53.0 °
Conc: 1 g/100mL; Solv: water ;  589.3 nm; Temp: 24 °C

IN

van den Nieuwendijk, Adrianus M. C. H.; Organic Letters 2010, 12(17), 3957-3959 

Abstract Image

The chemoenzymatic synthesis of three 1-deoxynojirimycin-type iminosugars is reported. Key steps in the synthetic scheme include a Dibal reduction−transimination−sodium borohydride reduction cascade of reactions on an enantiomerically pure cyanohydrin, itself prepared employing almond hydroxynitrile lyase (paHNL) as the common precursor. Ensuing ring-closing metathesis and Upjohn dihydroxylation afford the target compounds.

http://pubs.acs.org/doi/suppl/10.1021/ol101556k/suppl_file/ol101556k_si_002.pdf

COMPD 18

D-galacto-1-deoxynojirimicin.HCl (18).

D-N-Boc-6-OBn-galacto-1-deoxynojirimicin (159 mg, 0.450 mmol) was dissolved in a mixture of MeOH

(10 mL) and 6 M HCl (2 mL). The flask was purged with argon, Pd/C-10% (20 mg) was added and a balloon

with hydrogen gas was placed on top of the reaction. The mixture was stirred overnight at room temperature.

Pd/C was removed by filtration and the filtrate evaporated to yield the crude product (90 mg, 100%) as a

white foam that needed no further purification.

[α]24D = + 53.0 (c = 1, H2O);

[lit4a [α]24D = +44.6 (c = 0.9, H2O); lit4b [α]20D = +46.1 (c = 0.9, H2O)].

HRMS calculated for [C6H13NO4 + H]+164.09173; Found 164.09160.

1H NMR (400 MHz, D2O) δ 4.20 (dd, J = 2.7, 1.1 Hz, 1H), 4.11 (ddd, J = 11.4, 9.7, 5.4 Hz, 1H), 3.88 (ddd,

J = 20.9, 12.2, 6.8 Hz, 2H), 3.68 (dd, J = 9.7, 3.0 Hz, 1H), 3.55 (dd, J = 12.5, 5.4 Hz, 1H), 3.46 (ddd, J = 8.6,

4.8, 1.0 Hz, 1H), 2.97 – 2.86 (t, J = 12.0 Hz, 1H). [lit4c supporting information contains 1

H NMR-spectrumof an authentic sample].

13C NMR (101 MHz, D2O) δ 73.01, 66.97, 64.69, 60.16, 59.15, 46.15

4a) Ruiz, M.; Ruanova, T. M.; Blanco, O.; Núñez, F.; Pato, C.; Ojea, V. J. Org. Chem. 2008, 73, 2240

– 2255.

4b) Paulsen, H.; Hayauchi, Y.; Sinnwell, V. Chem. Ber. 1980, 113, 2601 – 2608. c)

McDonnell, C.; Cronin, L.; O’Brien, J. L.; Murphy, P. V. J. Org. Chem. 2004, 69, 3565 – 3568.

……………………………………….

(- ) FORM………… BE CAREFUL

Short and straightforward synthesis of (-)-1-deoxygalactonojirimycin

Org Lett 2010, 12(6): 1145

 http://pubs.acs.org/doi/abs/10.1021/ol100037c

Abstract Image

The mildness and low basicity of vinylzinc species functioning as a nucleophile in addition to α-chiral aldehydes is characterized by lack of epimerization of the vulnerable stereogenic center. This is demonstrated by a highly diastereoselective synthesis of 1-deoxygalactonojirimycin in eight steps from commercial starting materials with overall yield of 35%.

Figure

Figure 1. Structures of nojirimycin (1) and DGJ (2).

SEE SUPP INFO

http://pubs.acs.org/doi/suppl/10.1021/ol100037c/suppl_file/ol100037c_si_001.pdf

(-)-1-deoxygalactojirimycin hydrochloride as transparent colorless needles.

[α]D -51.4 (D2O, c 1.0)

1H-NMR (D2O) δ ppm 4.09 (dd, 1H, J 2.9 Hz, 1.3 Hz), 4.00 (ddd, 1H, J = 11.3 Hz, 9.7 Hz, 5.3 Hz),

3.80 (dd, 1H, J = 12,1 Hz, 8.8 Hz), 3.73 (dd, 1H, J = 12.1 Hz, 8.8 Hz), 3.56 (dd, 1H, J = 9.7 Hz, 2.9

Hz), 3.44 (dd, 1H, J = 12.4 Hz, 5.3 Hz), 3.34 (ddd, 1H, J = 8.7 Hz, 4.8 Hz, 1.0 Hz), 2.8 (app. t, 1H,

J = 12.0 Hz)

13C-NMR (D2O, MeOH iSTD) δ 73.6, 67.5, 65.3, 60.7, 59.7, 46.7

HRMS Measured 164.0923 (M + H – Cl) Calculated 164.0923 (C6H13NO4 + H – Cl)

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Links

Concise and highly stereocontrolled synthesis of 1-deoxygalactonojirimycin and its congeners using dioxanylpiperidene, a promising chiral building block

Org Lett 2003, 5(14): 2527

 http://pubs.acs.org/doi/abs/10.1021/ol034886y

Abstract Image

A concise and stereoselective synthesis of the chiral building block, dioxanylpiperidene 4 as a precursor for deoxyazasugars, starting from the Garner aldehyde 5 using catalytic ring-closing metathesis (RCM) for the construction of the piperidine ring is described. The asymmetric synthesis of 1-deoxygalactonojirimycin and its congeners 13 was carried out via the use of 4in a highly stereocontrolled mode.

 

mp 135-135.5 °C [lit.3mp 137-139 °C];

[α]D25 +27.8° (c 0.67, H2O)

[lit.3[α]D23 +28° (c 0.5, H2O)];

1H NMR (300 MHz, D2O) δ 2.59–2.65 (m, 1H), 2.81–2.87 (m, 1H),

3.02–3.08 (m, 1H), 3.46–3.48 (m, 2H), 3.59–3.66 (m, 3H); 13C NMR (75 MHz, D2O) δ 44.7, 57.1,

58.4, 70.9, 71.4, 73.3 [lit4 13C NMR (125 MHz, D2O) δ 44.5, 56.8, 58.3, 70.1, 70.7, 72.3];

HRMScalcd for C6H13NO4 (M+) 163.0855, Found 163.0843. Anal. calcd for C6H13NO4: C, 44.16; N,

8.58; H, 8.03. Found: C, 44.31; N, 8.55; H, 7.71.

3. Schaller, C.; Vogel, P.; Jager, V. Carbohydrate Res. 1998, 314, 25-35.

4. Lee, B. W.; Jeong, Ill-Y.; Yang, M. S.; Choi, S. U.; Park, K. H. Synthesis 2000, 1305-1309.

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Links

Applications and limitations of the I2-mediated carbamate annulation for the synthesis of piperidines: Five- versus six-membered ring formation

J Org Chem 2013, 78(19): 9791

http://pubs.acs.org/doi/abs/10.1021/jo401512h

Abstract Image

A protecting-group-free synthetic strategy for the synthesis of piperidines has been explored. Key in the synthesis is an I2-mediated carbamate annulation, which allows for the cyclization of hydroxy-substituted alkenylamines into piperidines, pyrrolidines, and furans. In this work, four chiral scaffolds were compared and contrasted, and it was observed that with both d-galactose and 2-deoxy-d-galactose as starting materials, the transformations into the piperidines 1-deoxygalactonorjirimycin (DGJ) and 4-epi-fagomine, respectively, could be achieved in few steps and good overall yields. When d-glucose was used as a starting material, only the furan product was formed, whereas the use of 2-deoxy-d-glucose resulted in reduced chemo- and stereoselectivity and the formation of four products. A mechanistic explanation for the formation of each annulation product could be provided, which has improved our understanding of the scope and limitations of the carbamate annulation for piperidine synthesis.

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Links

Ruiz, Maria; Journal of Organic Chemistry 2008, 73(6), 2240-2255 

http://pubs.acs.org/doi/abs/10.1021/jo702601z

ROT  +44.6 °  Conc: 0.9 g/100mL; Solv: water ;  589.3 nm; Temp: 24 °C

Abstract Image

A general strategy for the synthesis of 1-deoxy-azasugars from a chiral glycine equivalent and 4-carbon building blocks is described. Diastereoselective aldol additions of metalated bislactim ethers to matched and mismatched erythrose or threose acetonides and intramolecular N-alkylation (by reductive amination or nucleophilic substitution) were used as key steps. The dependence of the yield and the asymmetric induction of the aldol addition with the nature of the metallic counterion of the azaenolate and the γ-alkoxy protecting group for the erythrose or threose acetonides has been studied. The stereochemical outcome of the aldol additions with tin(II) azaenolates has been rationalized with the aid of density functional theory (DFT) calculations. In accordance with DFT calculations with model glyceraldehyde acetonides, hightrans,syn,anti-selectivitity for the matched pairs and moderate to low trans,anti,anti-selectivity for the mismatched ones may originate from (1) the intervention of solvated aggregates of tin(II) azaenolate and lithium chloride as the reactive species and (2) favored chair-like transition structures with a Cornforth-like conformation for the aldehyde moiety. DFT calculations indicate that aldol additions to erythrose acetonides proceed by an initial deprotonation, followed by coordination of the alkoxy-derivative to the tin(II) azaenolate and final reorganization of the intermediate complex through pericyclic transition structures in which the erythrose moiety is involved in a seven-membered chelate ring. The preparative utility of the aldol-based approach was demonstrated by application in concise routes for the synthesis of the glycosidase inhibitors 1-deoxy-d-allonojirimycin, 1-deoxy-l-altronojirimycin, 1-deoxy-d-gulonojirimycin, 1-deoxy-d-galactonojirimycin, 1-deoxy-l-idonojirimycin and 1-deoxy-d-talonojirimycin.

 

 

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Links

J. Org. Chem., 1991, 56 (2), pp 815–819
DOI: 10.1021/jo00002a057

http://pubs.acs.org/doi/abs/10.1021/jo00002a057

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Links

Hinsken, Werner; DE 3906463 A1 1990

http://www.google.com/patents/DE3906463A1?cl=de

Example 1 Preparation of 1,5-dideoxy-1,5-imino-D-glucitol hydrobromide

A suspension of 1,5-dideoxy-1,5-imino-D-glucitol (500 g) in isopropanol (2 l) with 48% hydrochloric acid, bromine (620 g). The suspension is stirred for 2 hours at 40 ° C, cooled to 0 ° C and the product isolated by filtration.

Yield: 700 g (93% of theory),
mp: 184 ° C.

Example 2 Preparation of 1,5-dideoxy-1,5-imino-D-mannitol hydrobromide

The prepared analogously to Example 1 from 1,5-dideoxy 1,5-imino-D-mannitol and 48% hydrobromic acid.

Yield: 89% of theory;

C₆H₁₄NO₄Br (244.1)
Ber .: C 29.5%; H 5.8%; N 5.7%; Br 32.7%;
vascular .: C 29.8%; H 5.8%; N 5.8%; Br 32.3%.

Example 3 Preparation of 1,5-dideoxy-1,5-imino-D-Galactitol- hydrochloride

The preparation was carried out analogously to Example 1 from 1,5-dideoxy-1,5-imino-D-galactitol and corresponding mole ratios of 37% hydrochloric acid.
yield: 91% of theory
, mp: 160-162 ° C.

 

Amat et al., “Eantioselective Synthesis of 1-deoxy-D-gluonojirimycin From A Phenylglycinol Derived Lactam,” Tetrahedron Letters, pp. 5355-5358, 2004.
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3   Encyclopedia of Chemical Technology, 4th Ed., 1995, John Wiley & Sons, vol. 14: p. 737-741.
4   Heiker et al., “Synthesis of D-galacto-1-deoxynojirimycin (1, 5-dideoxy-1, 5-imino-D-galactitol) starting from 1-deoxynojirimycin.” Carbohydrate Research, 203: 314-318, 1990.
5   Heiker et al., 1990, “Synthesis of D-galacto-1-deoxynojirimycin (1,5-dideoxy-1, 5-imino-D-galactitol) starting from 1-deoxynojirimycin,” Carbohydrate Research, vol. 203: p. 314-318.
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7 * Kinast et al. Angew. Chem. Int. Ed. Engl. 20 (1998), No. 9, pp. 805-806.
8 * Lamb, Laboratory Manual of General Chemistry, Harvard University Press, 1916, p. 108.
9   Linden et al., “1-Deoxynojirimycin Hydrochloride,” Acta ChrystallographicaC50, pp. 746-749, 1994.
10   Mellor et al., Preparation, biochemical characterization and biological properties of radiolabelled N-alkylated deoxynojirimycins, Biochem. J. Aug. 15, 2002; 366(Pt 1):225-233.
11 * Mills, Encyclopedia of Reagents for Organic Synthesis, Hydrochloric Acid, 2001 John Wily & Sons.
12   Santoyo-Gonzalez et al., “Use of N-Pivaloyl Imidazole as Protective Reagent for Sugars.” Synthesis 1998 1787-1792.
13   Schuller et al., “Synthesis of 2-acetamido-1, 2-dideoxy-D-galacto-nojirimycin (2-acetamido-1, 2, 5-trideoxy-1, 5-imino-D-galacitol) from 1-deoxynojirimycin.” Carbohydrate Res. 1990; 203: 308-313.
14   Supplementary European Search Report dated Mar. 11, 2010 issued in corresponding European Patent Application No. EP 06 77 2888.
15   Uriel et al., A Short and Efficient Synthesis of 1,5-dideoxy-1,5-imino-D-galactitol (1-deoxy-D-galactostatin) and 1,5-dideoxy-1,5-dideoxy-1,5-imino-L-altritol (1-deoxy-L-altrostatin) From D-galactose, Synlett (1999), vol. 5, pp. 593-595.

 

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(i) Aoyagi, S.; Fujimaki, S.; Yamazaki, N.; Kibayashi, C. J. Org. Chem. 199156, 815−819.

(j) Kajimoto, T.; Chen, L.; Liu, K. K. C.; Wong, C. H. J. Am. Chem. Soc1991113, 6678−6680.

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(l) Singh, O. V.; Han, H. Tetrahedron Lett. 200344, 2387−2391.

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