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All 11 posts Subject: Hydroxycodeinone>Oxycodone(Sodium hydrosulfite) Please login to post Down

merbst
(Stranger)
11-08-03 10:26
No 469624
      Hydroxycodeinone>Oxycodone(Sodium hydrosulfite)
(Rated as: good read)

14-Hydroxycodeinone -> Oxycodone via Sodium hydrosulfite:

------------- Found in "Oxy" by Otto Snow pg 36: ----------------

By Martin Freund (1924) Patent US1479293 Patent DE296916
10 grams oxycodeinon (14-hydroxycodeinone) are heated with a solution of 20 grams sodium hydrosulfite (Na2S2O4) in 60 ml water. After a short time complete solution takes place. Upon supersaturating with soda or ammonia 6 grams oxycodone are separated in crystalline form.
Dihydrooxycodeinon (Oxycodone)... crystallizes from alcohol in long jagged columns melting at 222C and yields well crystallized salts. Its hydrochloride C18H20NO4*HCL crystallizes from water or diluted alcohol in columns melting at 268C to 270C. Its free base is precipitated from solutions of the salt by ammonia, soda or alkalies; it is insoluble in excess of alkalies.

References
Freund, Walter (1924) Product of Reduction of Oxycodeinon and Process of Preparing the Same; Merck Index 13th edition (1996) Oxycodone; Dihydrothebenine from thebenine and sodium hydrosulfite, see Speyer and Rosenfeld, Ber (1925) 58, 1120.
Note: Other sulfites might also work [sic?]. See page 47.

------------- Found in "Oxy" by Otto Snow pg 47: ----------------

Etorphine
Process of purifying Oripavines
by Willian R. Hydro,
assignor to the United States of America
as represented by the Secretary of the Army
Patent US3763167

- snip -

The procedure in (a) [sodium metabisulfite] was repeated with the substitution of sodium bisulfite, sodium hydrosulfite, sodium sulfite, or sodium thiosulfite ...

- snip -

------------- My commentary -------------------------------------

Why this is important:
After extensively UTFSE on rhodium.ws and the-hive.ws and google.com for: (hydroxycodeinone AND hydrosulfite) OR (hydroxycodeinone AND dithionite), this reference was never turned up.
Sodium hydrosulfite (aka Sodium Dithionite) can be found OTC at many major supermarkets, and european bees may be able to find it in relation to reducing indigo.
Catalytic hydrogenation is no longer necessary; one does not need to obtain Pd/C or a hydrogen supply.
The patent provides information not included in this short summary, and references a "patent application of Serial Number 485130 filed July 15, 1921, from which this is a divisional application.", indicating that there is more, but I do not know how to find the parent patent.
Theoretically oxy could be created using only things found at a supermarket and a lot of patience. (poppy seeds + 6 months + thebaine extraction + hydrogen peroxide purification + vinegar purification + hydrosulfite + ammonia) laugh

My thoughts about this book:
When I first received this book, I was disappointed, as I bought this book to learn more about the pharmacology of Oxycodone, yet the Oxycodone section is pages 31-42, and only the first 2 of those are pharmacology! Most of the book deals with various species and relatives of papaver which produce alkaloids resembling morphine. However upon closer inspection the references within the chemical section are NOT the same ones available on Rhodium's fine site. It has this one, plus roughly 2 unique routes from thebaine to 14-hydroxycodeinone, plus interesting material regarding the synthesis of Etorphine and the extraction of thebaine. I will be typing out anything else I find that is relevant soon.
I fail to see how Otto Snow believes the Etorphine patent to indicate that other sulfites might also work, but then again I'm not a chemist. wink

Note: the Na hydrosulfite found in the laundry aisle also contains sodium carbonate anhydrous. I assume this is to reduce the risk of fire due to spontaneous combustion upon contact with moisture in the atmosphere.

My questions from this are:
Out of curiosity, what is the activity of 14-hydroxycodeinone? The MSDS (http://bulkpharm.mallinckrodt.com/_attachments/msds/OXONN.htm) calls it a Narcotic with human lethal dose of 120-250mg.
Is Oxycodone base orally active?
How do I find a patent based on the serial number of its patent application?
I've read that buprenorphine is produced from 14-hydroxycodeinone, does anybody know how?

Enjoy!

Rhodium
(Chief Bee)
11-09-03 01:38
No 469693
User Picture       opioids & patents

Is Oxycodone base orally active?

Sure, it turns into a soluble salt in the stomach acid.

How do I find a patent based on the serial number of its patent application?

You fill out the form here: http://gb.espacenet.com/espacenet/gb/en/e_net.htm?search5

fierceness
(Hive Addict)
11-09-03 07:05
No 469750
      Wow!

Excellent find. That means you can go from codeine to codeinone through a simple oxidation (MnO2) and then to 14-hydroxycodeinone with H202 and formic acid with the final step being this procedure.

hellman
11-10-03 01:20
      well done,
(Rated as: insignificant)

Rhodium
(Chief Bee)
11-11-03 22:16
No 470282
User Picture       Codeinone to Oxycodone/Oxymorphone
(Rated as: excellent)

Studies Into the Direct Oxidation of Codeinone to 14-Hydroxycodeinone
Andrew Coop and Kenner C. Rice
Tetrahedron 55, 11429-11436 (1999) (https://www.rhodium.ws/pdf/codeinone2hydroxycodeinone.pdf)

Abstract
The direct oxidation of codeinone (5) to 14-hydroxycodeinone (6) was investigated with a wide range of oxidizing agents. The majority of reagents gave little or no desired product. Peracids were found to be moderately successful, with dimethyl peracetic acid giving the greatest yield (37%). Metallic oxidants generally gave rise to competing oxidations, however Co(AcO)₃ was found to conveniently oxidize 5 to 6 in 51% yield, representing a practical, non-chromatographic procedure for the preparation of 14-hydroxycodeinone.
_____ ___ __ _

L-Selectride as a General Reagent for the O-Demethylation and N-Decarbomethoxylation of Opium Alkaloids and Derivatives
Coop, A.; Janetka, J. W.; Lewis, J. W.; Rice, K. C.
J. Org. Chem. 63(13), 4392-4396 (1998) (https://www.rhodium.ws/pdf/opium.alkaloid.o-demethylation.pdf)
DOI:10.1021/jo9801972

merbst
(Stranger)
11-18-03 10:22
No 471551
      14-hydroxycodeinone & 14-hydroxymorphinone
(Rated as: excellent)

(TFSE has been U'd)
Patent US6008355 Preparation of oxycodone from codeine
   A process is provided for preparing oxycodone from codeine comprising either: (A) the steps of (1) oxidizing codeine so as to form codeinone; (2) converting codeinone to oxycodone in a two-step-one-pot reaction: first reacting codeinone with hydrogen peroxide in water in the presence of an acid at from about 15 DEG to about 70 DEG C. to form 14-hydroxycodeinone and then catalytically hydrogenating 14-hydroxycodeinone in its original reaction mixture to form oxycodone; or (B) the steps of (1) oxydizing codeine so as to form codeinone; (2) reacting codeinone with an acylating agent so as to form codeinone dienol acylate; (3) oxidizing codeinone dienol acylate with an oxidation agent in water or a solubilizing solvent mixture in the presence of an acid at from about 15 DEG to about 70 DEG C. to form 14-hydroxycodeinone; (4) hydrogenating 14-hydroxycodeinone in its original reaction mixture to form oxycodone.
   This patent covers the methods in http://rhodium.ws/chemistry/oxycodone.html http://rhodium.ws/pdf/hydroxycodeinone-1.pdf
   This patent provides information beyond other references, including 47 Example preparations of interesting substances such as naltrexone, noroxymorphone, and norcodeine.
   I'd like to bring attention to "catalytically hydrogenating 14-hydroxycodeinone in its original reaction mixture to form oxycodone", would this apply when the hydrogenation is done using Sodium Hydrosulfite?
   A text version of the patent is here: http://www.poppies.org/news/99502122134978.shtml

Patent US5922876 Preparation of oxymorphone from morphine
   A process is provided for preparing oxymorphone from morphine by: (a) reacting morphine with an acyl halide or anhydride to form 3-acylmorphine, or (b) reacting morphine with benzyl-halide to form 3-benzylmorphine, and thereafter either by (3a) or (3b): (3a) introducing a beta -oriented hydroxy group at the 14-position of the 3-acyl- or 3-benzyl-morphinone with aqueous hydrogen peroxide and an acid at at temperature of about 15 DEG to about 70 DEG C. to form the 3-acyl or 3-benzyl-14-hydroxymorphinone; (3b) acylating the 3-acyl or 3-benzyl-morphinone with an acylating agent so as to form the dienol acylate followed by oxidizing the dienol acetate to the corresponding 3-acyl or 3-benzyl-14-hydroxymorphinone; (4) hydrogenating the 3-acyl-14-hydroxymorphinone with a catalyst so as to form the 3-acyloxymorphone; (5) hydrolyzing the 3-acyl-oxymorphone with aqueous acidic or basic solution to form oxymorphone; (6) hydrogenating the 3-benzyl-14-hydroxymorphinone with a catalyst so as to form oxymorphone.
   This is roughly analougous to the oxycodone patent, and I was wondering if the reduction via Sodium Hydrosulfite would also apply here?

Medline (PMID=172013)
   This is an unusual route to the above 2 substances, using enzymes.

I hope somebody finds these things useful, tomorrow I will attempt to answer my own question about buprenorphine, and then comes some interesting potent simple analogs of morphine.

merbst
(Stranger)
11-18-03 10:33
No 471554
      14-hydroxycodeinone -> oxymorphone !!!
(Rated as: good read)

There goes any chance of waking up on time for work... This one was so good it needed its own post:
Patent US2772270 Provides a method for converting 14-hydroxycodeinone to 14-hydroxymorphinone and a method for converting 14-hydroxycodeinone to 8,14-dihydroxy-hydroxymorphinone (oxymorphone) and its salts using HBr.
Wow!

SPISSHAK
(Hive Addict)
02-29-04 06:12
No 491721
      codeine to codeinone in 95% yeild using 6N HCL
(Rated as: good read)

and gamma MnO2 in isopropanol
US2001018519

http://v3.espacenet.com/origdoc?DB=EPODOC&IDX=US2001018519&QPN=US2001018519

examples of conversion of thebaine to14-hydroxycodeinone in one step using peracids are referenced
1) J. MED Chem 1978, 21, 398
2)J MED Chem 1974, 17, 1117
3) J. Org Chem 1981, 24, 1525

This one is really interesting, it pertains to tissue cell cultures of papaver bracteum and extration of thebaine therefrom.

http://l2.espacenet.com/espacenet/bnsviewer?CY=ep&LG=en&DB=EPD&PN=US4114314&ID=US+++4114314A1+I+

merbst
(Hive Bee)
03-02-04 09:21
No 492264
      Thank you Spisshak, although be aware that...

Thank you Spisshak, although be aware that many of the US2001... style patents are duplicates of existing US600... patents. Also, the [patent] tag makes referencing espacenet much easier. Not saying that what you provided isn't useful! Thanks! You have a PM coming. :-D

Correction to the post 2 above this one: While the reference I posted is extremely useful for experimental details in 3-O-Demethylation of morphinans using HBr, I was incorrect in that 8,14-dihydroxy-hydroxymorphinone is NOT oxymorphone, instead it is a product which may be converted back into 14-hydroxymorphinone by the addition of dilute aqueous HCl. It is no closer to oxymorphone than 14-hydroxymorphinone is however.

Yoff
(Stranger)
03-09-04 23:03
No 494047
      10 grams oxycodeinon (14-hydroxycodeinone) are

10 grams oxycodeinon (14-hydroxycodeinone) are heated with a solution of 20 grams sodium hydrosulfite (Na2S2O4) in 60 ml water. After a short time complete solution takes place. Upon supersaturating with soda or ammonia 6 grams oxycodone are separated in crystalline form.Would someone be so kind to explain the mechanism of this rxn, please?

wolff_kishner
(Newbee)
11-02-04 19:28
No 539245
      Would it work to make hydrocodone also?

Would this reaction also work to make hydrocodone if an equimolar amount of codeinone were substituted for 14-hydroxycodeinone?

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	All 11 posts		Subject: Hydroxycodeinone>Oxycodone(Sodium hydrosulfite)		Please login to post		Down


		merbst (Stranger) 11-08-03 10:26 No 469624				Hydroxycodeinone>Oxycodone(Sodium hydrosulfite) (Rated as: good read)
						14-Hydroxycodeinone -> Oxycodone via Sodium hydrosulfite: ------------- Found in "Oxy" by Otto Snow pg 36: ---------------- By Martin Freund (1924) Patent US1479293 Patent DE296916 10 grams oxycodeinon (14-hydroxycodeinone) are heated with a solution of 20 grams sodium hydrosulfite (Na2S2O4) in 60 ml water. After a short time complete solution takes place. Upon supersaturating with soda or ammonia 6 grams oxycodone are separated in crystalline form. Dihydrooxycodeinon (Oxycodone)... crystallizes from alcohol in long jagged columns melting at 222C and yields well crystallized salts. Its hydrochloride C18H20NO4*HCL crystallizes from water or diluted alcohol in columns melting at 268C to 270C. Its free base is precipitated from solutions of the salt by ammonia, soda or alkalies; it is insoluble in excess of alkalies. References Freund, Walter (1924) Product of Reduction of Oxycodeinon and Process of Preparing the Same; Merck Index 13th edition (1996) Oxycodone; Dihydrothebenine from thebenine and sodium hydrosulfite, see Speyer and Rosenfeld, Ber (1925) 58, 1120. Note: Other sulfites might also work [sic?]. See page 47. ------------- Found in "Oxy" by Otto Snow pg 47: ---------------- Etorphine Process of purifying Oripavines by Willian R. Hydro, assignor to the United States of America as represented by the Secretary of the Army Patent US3763167 - snip - The procedure in (a) [sodium metabisulfite] was repeated with the substitution of sodium bisulfite, sodium hydrosulfite, sodium sulfite, or sodium thiosulfite ... - snip - ------------- My commentary ------------------------------------- Why this is important: After extensively UTFSE on rhodium.ws and the-hive.ws and google.com for: (hydroxycodeinone AND hydrosulfite) OR (hydroxycodeinone AND dithionite), this reference was never turned up. Sodium hydrosulfite (aka Sodium Dithionite) can be found OTC at many major supermarkets, and european bees may be able to find it in relation to reducing indigo. Catalytic hydrogenation is no longer necessary; one does not need to obtain Pd/C or a hydrogen supply. The patent provides information not included in this short summary, and references a "patent application of Serial Number 485130 filed July 15, 1921, from which this is a divisional application.", indicating that there is more, but I do not know how to find the parent patent. Theoretically oxy could be created using only things found at a supermarket and a lot of patience. (poppy seeds + 6 months + thebaine extraction + hydrogen peroxide purification + vinegar purification + hydrosulfite + ammonia) My thoughts about this book: When I first received this book, I was disappointed, as I bought this book to learn more about the pharmacology of Oxycodone, yet the Oxycodone section is pages 31-42, and only the first 2 of those are pharmacology! Most of the book deals with various species and relatives of papaver which produce alkaloids resembling morphine. However upon closer inspection the references within the chemical section are NOT the same ones available on Rhodium's fine site. It has this one, plus roughly 2 unique routes from thebaine to 14-hydroxycodeinone, plus interesting material regarding the synthesis of Etorphine and the extraction of thebaine. I will be typing out anything else I find that is relevant soon. I fail to see how Otto Snow believes the Etorphine patent to indicate that other sulfites might also work, but then again I'm not a chemist. Note: the Na hydrosulfite found in the laundry aisle also contains sodium carbonate anhydrous. I assume this is to reduce the risk of fire due to spontaneous combustion upon contact with moisture in the atmosphere. My questions from this are: Out of curiosity, what is the activity of 14-hydroxycodeinone? The MSDS (http://bulkpharm.mallinckrodt.com/_attachments/msds/OXONN.htm) calls it a Narcotic with human lethal dose of 120-250mg. Is Oxycodone base orally active? How do I find a patent based on the serial number of its patent application? I've read that buprenorphine is produced from 14-hydroxycodeinone, does anybody know how? Enjoy!



		Rhodium (Chief Bee) 11-09-03 01:38 No 469693				opioids & patents
						Is Oxycodone base orally active? Sure, it turns into a soluble salt in the stomach acid. How do I find a patent based on the serial number of its patent application? You fill out the form here: http://gb.espacenet.com/espacenet/gb/en/e_net.htm?search5



		fierceness (Hive Addict) 11-09-03 07:05 No 469750				Wow!
						Excellent find. That means you can go from codeine to codeinone through a simple oxidation (MnO2) and then to 14-hydroxycodeinone with H202 and formic acid with the final step being this procedure.



		hellman 11-10-03 01:20				well done, (Rated as: insignificant)



		Rhodium (Chief Bee) 11-11-03 22:16 No 470282				Codeinone to Oxycodone/Oxymorphone (Rated as: excellent)
						Studies Into the Direct Oxidation of Codeinone to 14-Hydroxycodeinone Andrew Coop and Kenner C. Rice Tetrahedron 55, 11429-11436 (1999) (https://www.rhodium.ws/pdf/codeinone2hydroxycodeinone.pdf) Abstract The direct oxidation of codeinone (5) to 14-hydroxycodeinone (6) was investigated with a wide range of oxidizing agents. The majority of reagents gave little or no desired product. Peracids were found to be moderately successful, with dimethyl peracetic acid giving the greatest yield (37%). Metallic oxidants generally gave rise to competing oxidations, however Co(AcO)₃ was found to conveniently oxidize 5 to 6 in 51% yield, representing a practical, non-chromatographic procedure for the preparation of 14-hydroxycodeinone. _____ ___ __ _ L-Selectride as a General Reagent for the O-Demethylation and N-Decarbomethoxylation of Opium Alkaloids and Derivatives Coop, A.; Janetka, J. W.; Lewis, J. W.; Rice, K. C. J. Org. Chem. 63(13), 4392-4396 (1998) (https://www.rhodium.ws/pdf/opium.alkaloid.o-demethylation.pdf) DOI:10.1021/jo9801972



		merbst (Stranger) 11-18-03 10:22 No 471551				14-hydroxycodeinone & 14-hydroxymorphinone (Rated as: excellent)
						(TFSE has been U'd) Patent US6008355 Preparation of oxycodone from codeine A process is provided for preparing oxycodone from codeine comprising either: (A) the steps of (1) oxidizing codeine so as to form codeinone; (2) converting codeinone to oxycodone in a two-step-one-pot reaction: first reacting codeinone with hydrogen peroxide in water in the presence of an acid at from about 15 DEG to about 70 DEG C. to form 14-hydroxycodeinone and then catalytically hydrogenating 14-hydroxycodeinone in its original reaction mixture to form oxycodone; or (B) the steps of (1) oxydizing codeine so as to form codeinone; (2) reacting codeinone with an acylating agent so as to form codeinone dienol acylate; (3) oxidizing codeinone dienol acylate with an oxidation agent in water or a solubilizing solvent mixture in the presence of an acid at from about 15 DEG to about 70 DEG C. to form 14-hydroxycodeinone; (4) hydrogenating 14-hydroxycodeinone in its original reaction mixture to form oxycodone. This patent covers the methods in http://rhodium.ws/chemistry/oxycodone.html http://rhodium.ws/pdf/hydroxycodeinone-1.pdf This patent provides information beyond other references, including 47 Example preparations of interesting substances such as naltrexone, noroxymorphone, and norcodeine. I'd like to bring attention to "catalytically hydrogenating 14-hydroxycodeinone in its original reaction mixture to form oxycodone", would this apply when the hydrogenation is done using Sodium Hydrosulfite? A text version of the patent is here: http://www.poppies.org/news/99502122134978.shtml Patent US5922876 Preparation of oxymorphone from morphine A process is provided for preparing oxymorphone from morphine by: (a) reacting morphine with an acyl halide or anhydride to form 3-acylmorphine, or (b) reacting morphine with benzyl-halide to form 3-benzylmorphine, and thereafter either by (3a) or (3b): (3a) introducing a beta -oriented hydroxy group at the 14-position of the 3-acyl- or 3-benzyl-morphinone with aqueous hydrogen peroxide and an acid at at temperature of about 15 DEG to about 70 DEG C. to form the 3-acyl or 3-benzyl-14-hydroxymorphinone; (3b) acylating the 3-acyl or 3-benzyl-morphinone with an acylating agent so as to form the dienol acylate followed by oxidizing the dienol acetate to the corresponding 3-acyl or 3-benzyl-14-hydroxymorphinone; (4) hydrogenating the 3-acyl-14-hydroxymorphinone with a catalyst so as to form the 3-acyloxymorphone; (5) hydrolyzing the 3-acyl-oxymorphone with aqueous acidic or basic solution to form oxymorphone; (6) hydrogenating the 3-benzyl-14-hydroxymorphinone with a catalyst so as to form oxymorphone. This is roughly analougous to the oxycodone patent, and I was wondering if the reduction via Sodium Hydrosulfite would also apply here? Medline (PMID=172013) This is an unusual route to the above 2 substances, using enzymes. I hope somebody finds these things useful, tomorrow I will attempt to answer my own question about buprenorphine, and then comes some interesting potent simple analogs of morphine.



		merbst (Stranger) 11-18-03 10:33 No 471554				14-hydroxycodeinone -> oxymorphone !!! (Rated as: good read)
						There goes any chance of waking up on time for work... This one was so good it needed its own post: Patent US2772270 Provides a method for converting 14-hydroxycodeinone to 14-hydroxymorphinone and a method for converting 14-hydroxycodeinone to 8,14-dihydroxy-hydroxymorphinone (oxymorphone) and its salts using HBr. Wow!



		SPISSHAK (Hive Addict) 02-29-04 06:12 No 491721				codeine to codeinone in 95% yeild using 6N HCL (Rated as: good read)
						and gamma MnO2 in isopropanol US2001018519 http://v3.espacenet.com/origdoc?DB=EPODOC&IDX=US2001018519&QPN=US2001018519 examples of conversion of thebaine to14-hydroxycodeinone in one step using peracids are referenced 1) J. MED Chem 1978, 21, 398 2)J MED Chem 1974, 17, 1117 3) J. Org Chem 1981, 24, 1525 This one is really interesting, it pertains to tissue cell cultures of papaver bracteum and extration of thebaine therefrom. http://l2.espacenet.com/espacenet/bnsviewer?CY=ep&LG=en&DB=EPD&PN=US4114314&ID=US+++4114314A1+I+



		merbst (Hive Bee) 03-02-04 09:21 No 492264				Thank you Spisshak, although be aware that...
						Thank you Spisshak, although be aware that many of the US2001... style patents are duplicates of existing US600... patents. Also, the [patent] tag makes referencing espacenet much easier. Not saying that what you provided isn't useful! Thanks! You have a PM coming. :-D Correction to the post 2 above this one: While the reference I posted is extremely useful for experimental details in 3-O-Demethylation of morphinans using HBr, I was incorrect in that 8,14-dihydroxy-hydroxymorphinone is NOT oxymorphone, instead it is a product which may be converted back into 14-hydroxymorphinone by the addition of dilute aqueous HCl. It is no closer to oxymorphone than 14-hydroxymorphinone is however.



		Yoff (Stranger) 03-09-04 23:03 No 494047				10 grams oxycodeinon (14-hydroxycodeinone) are
						10 grams oxycodeinon (14-hydroxycodeinone) are heated with a solution of 20 grams sodium hydrosulfite (Na2S2O4) in 60 ml water. After a short time complete solution takes place. Upon supersaturating with soda or ammonia 6 grams oxycodone are separated in crystalline form.Would someone be so kind to explain the mechanism of this rxn, please?



		wolff_kishner (Newbee) 11-02-04 19:28 No 539245				Would it work to make hydrocodone also?
						Would this reaction also work to make hydrocodone if an equimolar amount of codeinone were substituted for 14-hydroxycodeinone?

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