PolytheneSam
(Master Searcher)
12-06-02 16:23
No 387007
      oximes
(Rated as: excellent)
 Bookmark   

Formation of oximes from carbonyl compounds (ketones or aldehydes).  The patents were found in 564/259.

Patent US2237365 high yield, oximes
Patent US2283150 example with 95% yield
Patent US2350318 ex. 4 Raney Ni
Patent US2562205 > 90% yield
Patent US3429920 buffered medium
Patent US3457354 2,4,5-trimethoxyamphetamine ex III A & B
Patent US3808275 presence of tin compound
Patent US3821303 NH2OH produced in situ
Patent US4015011 amphetamines, ex. 12 oxime
Patent US4707294 NH2OH in alcohol
Patent US6235935 high purity/yields
Patent US6462235 ketone, H2O2, NH3, catalyst


http://www.geocities.com/dritte123/PSPF.html
The hardest thing to explain is the obvious
 
 
 
 
    PolytheneSam
(Master Searcher)
12-07-02 09:34
No 387159
      oxime reduction  Bookmark   

Here's something from
Chemische Berichte vol. 26 page 1904 (1893)
on the reduction of phenylacetoxime with sodium amalgam


 
    beta-Phenyläthylamin

     Eine alkololische Lösung von 9.4 g Phenylacetoxim wurde nach un nach mit 500 g 2 1/2 pCt. Natriumamalgam versetzt und die Flüssigkeit durch Zugiessen von Eisesssig stets angesäuert.  Ueberschreitet die Temperatur der Lösung nicht 20º, so ist bei dem Zusatze der ersten Hälfte des Amalgams nur eine geringe, beim Hinzufügen der zweiten Hälfte aber eine lebhafte Wasserstoffentwicklung wahrzunehmen.
     Die gelb gefärbte Flüssigkeit wurde nach der Reduction von dem Alkohol durch Eindampfen befreit und der Rückstand mit Wasser erwärmt.  Ungelöst blieb etwas unverändertes Oxim; das Filtrat schied auf Zugabe von Kalilauge ein aufschwimmendes braun gefärbtes Oel ab, das nach dem Trennen mittels Aether fractionirt wurde.  Farbloses Liquidum vom Siedepunkt 197-198º bei 725 Druck.
     Ausbeute 7.5 g vom destillirten Amin, was etwa 90 pCt. der theoretischen Menge entspricht.
     Das Phenyläthylamin wurde in die Acetyl- und Benzoylverbindung übergeführt und diese mit Phosphorpentoxyd zu den Dihydroisochinolinderivaten condensirt.



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The hardest thing to explain is the obvious
 
 
 
 
    PolytheneSam
(Master Searcher)
12-07-02 09:56
No 387162
      translation  Bookmark   

Here's my translation/interpretation:

     An alcoholic solution of 9.4 g phenylacetoxime was gradually added to 500 g of sodium amalgam and the liquid was kept acid by addition of glacial acetic acid.  The temperature stayed under 20º. When the first half of the amalgam was added there was little reaction, but after the second half of the amalgam was added there was a vigorous production of hydrogen.
     The yellow colored liquid was freed from the alcohol after the reduction by evaporation and the residue was warmed in water.  Unreacted oxime remained undissolved.  The filtrate when treated with KOH produced a brown oil (floating on top), after separation of ether medium (extracted with ether?).  Colorless liquid bp 197-198º at 725 pressure.
     Yield 7.5 g of distilled amine, about 90 % theoretical corresponding amount.
     The phenylethylamine was converted to the acetyl and benzoyl derivatives and condensed to dihydroisoquinoline derivatives using phosphorus pentoxide.


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The hardest thing to explain is the obvious
 
 
 
 
    Osmium
(Stoni's sexual toy)
12-07-02 13:05
No 387206
      Corrections: The amalgam was added to the ...  Bookmark   

Corrections:
The amalgam was added to the solution of oxime in EtOH.

IF the temperature was kept below 20°C THEN this two stage H2 development was observable.

...brown oil (floating on top), which was fractionated after being extracted with ether.

I'm not fat just horizontally disproportionate.
 
 
 
 
    PolytheneSam
(Master Searcher)
12-16-02 17:24
No 390120
      reduction to amines  Bookmark   

One reference I have says oximes can be reduced using NaHg/EtOH114, aluminum amalgam57 and zinc and acetic acid122 (among other ways).

references:
 
57. Cerchez and Dumitresco-Colesiu, Bull. soc. chim., (5) 1, 852 (1934)

114. Houben-Weyl, Die Methoden der organischen Chemie, (II) p. 350 (1925)

122. Kanao, J. Pharm. Soc. Japan, 49, 157 (1929): 50, 24 (1930)

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The hardest thing to explain is the obvious
 
 
 
 
    hypo
(Hive Addict)
12-17-02 02:08
No 390183
      aldoximes vs. ketoximes  Bookmark   

can one say that methods reducing aldoximes will usually also reduce
ketoximes?
 
 
 
 
    Rhodium
(Chief Bee)
12-17-02 14:51
No 390325
      Yes, generally. However, the other way around ...  Bookmark   

Yes, generally. However, the other way around might be a little tricky sometimes, for example in the Varma/Kabalka SnCl2 reduction.
 
 
 
 
    PolytheneSam
(Master Searcher)
12-18-02 16:22
No 390628
      catalytic hydrogenation  Bookmark   

http://community.webshots.com/photo/28229010/38035795iPyrNq

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The hardest thing to explain is the obvious
 
 
 
 
    PolytheneSam
(Master Searcher)
12-25-02 12:06
No 392780
      more on NaHg/CH3COOH reduction  Bookmark   

This patent gives an example for reducing vanillyl oxime to the amine using NaHg/CH3COOH.
Patent US1329272
BTW, you can make sodium amalgam by electrolysing an aqueous NaOH solution using a mercury cathode (ie. at the bottom of a beaker with an insulated wire (bare at the end) going into the mercury like I tried many beers ago with success).  Air and H2O decomposes NaHg so its best to use it asap or store it in an inert atmosphere or under mineral oil, etc.

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The hardest thing to explain is the obvious
 
 
 
 
    Barium
(Hive Bee)
01-07-03 05:51
No 396128
      Another one!  Bookmark   

Please tell me this patent hasn´t been posted before. No hits in TFSE anyway.

Patent GB1062299

1-(3,4-dihydroxyphenyl)-2-propanone oxime is made from the nitrostyrene
and reduced to the N-hydroxyamphetamine under very mild conditions.
I don´t need to mention what can be made from this amphetamine very easily.
Do I? wink

Catalytic hydrogenation freak
 
 
 
 
    Aurelius
(Hive Addict)
01-09-03 09:09
No 396700
      For PolytheneSam, US pat 2237365  Bookmark   

US patent 2237365

Production of Oximes

Example 1:

In a tank provided with a cooling jacket, a solution of 38 moles of hydroxylamine sulfate in 15 liters of water is stirred with 7 kilos of cyclohexanone (containing 2 % of cyclohexanol) and a potassium carbonate solution of 33% strength is added at temps between 0-10*C until congo red paper is just no longer dyed blue while the solution remains acid to litmus.  The mixture, which has become pulpy because of the separated oxime crystals, is stirred for another 30 minutes, filtered and carefully washed with as little water as possible.  To the filtrate there is added immediately another 0.7 kilogram of cyclohexanone and the neutralizing continued at about 10*C.  until the solution again only just reacts to litmus.  The last neutralization of the acid can advantageously be carried out with alkali metal acetate or another buffer salt.

The non- aqueous phase, consisting of cyclohexanone, cyclohexanone oxime and cyclohexanol is removed by distilling with steam.  The oxime is extracted from the oil layer in the distillate by means of lye and returned together with the lye into the first step of the process.  The mixture of ketone and alcohol which is free from oxime is converted into pure ketone by dehydrogenation.  The cyclohexanone oxime obtained in practically quantitative yield is chemically pure.  In the same manner the oximes of the isomeric methyl cyclohexanones are obtained.

Example 2:

A mixture of ketones obtained by hydrogenating technical cresole followed by oxidation of the hydrogenation product is mixed with 10% of the calculated amount of hydroxylamine sulfate in aqueous solution of 15% strength.  While stirring strongly the mixture is neutralized at 0-5*C. with strong soda lye until its reaction is only just acid to litmus and the oily oxime mixture, which is practically free of ketones, is separated.  After a new proportion of ketone mixture has been added, the neutralization of the further liberated mineral acid is completed with sodium acetate.  The separated oil is treated with alkali as in Example 1 to remove the oxime.  The alcohol-containing ketone mixture is subjected to dehydrogenation.  In this case, also, the yield is practically quantitative. 

Example 3:

An aqueous solution of hydroxylamine sulfate is mixed with a solution of d-menthone in DCM and the mixture neutralized while stirring at 0-10*C. by gradually adding strong soda lye, the latter being replaced by sodium acetate at the end, when congo red paper is only colored grey.  After removing the DCM by distilling a low vacuum the d-menthone oxime formed is filtered off.  It is practically free from ketones.  The rest of the hydroxylamine is reacted by adding a further amount of d-menthone in DCM and neutralizing again.  The mixture of d-menthone and d-menthone oxime thus obtained is returned to step 1.

No other substantially different examples were left in the patent.


 
 
 
 
    Aurelius
(Hive Addict)
01-09-03 09:28
No 396704
      US patent 2283150, oxime production  Bookmark   

US patent 2283150

Process of Producing Oximes


Example 1:

Into a vessel provided with a stirrer and a cooling jacket there are introduced 100 mol of cyclohexanone of 98 % purity and 105 moles of hydroxylamine in the form of hydroxylamine sulfate solution containing 170 grams of hydroxylamine base per liter.  The mixture is well stirred as the oxime already begins to separate.  Into this mixture there is poured slowly, while stirring and cooling, aqueous ammonia of strength 30%, care being taken that the temp does not rise above 25*C.  It is essential for a good yield of the product that local concentration of high alkalinity in the reaction be avoided.  It is therefore advantageous to introduce the ammonia simultaneously at different places preferably below the surface of the reaction liquid.  The neutralization is continued until the mixture is just no longer acid to congo red but still acid to litmus.  The reaction mixture is washed several times with small amounts of ice water.  The yield of practically pure product is about 95% theory (calc on ketone). 

Only example given.

 
 
 
 
    Aurelius
(Hive Addict)
01-09-03 09:57
No 396708
      US patent 2562205
(Rated as: excellent)
 Bookmark   

US patent 2562205

Process for Producing Oximes


Preparation of Hydroxylamine sulfonate:

For this purpose, 840g of technical sodium nitrite is mixed with 7 kilograms of split ice to a paste.  Then a solution of bisulphite, obtained by saturation of a solution of 660g of sodium carbonate (anhydrous) in 2 liters of water with sulfur dioxide added.  Within 40 minutes the whole amount of the bisulphite solution is added.  Thereafter, the sulfur dioxide is led in until the brown color disappears and the acid reaction on congo takes place.  This is done while the reaction mixture is continuously agitated and while the temp is held under 0*C.  after 6.3 kilograms of ice are added.  After 2 hours the saturation is completed.  The solution , at –2*C, is filtered and used to prepare different oximes in the following examples.


Example 1:

860cc of hydroxylamine sulfonate solution (as above) is shaken at 5*C with 45g of cyclohexanone for such a period of time as to make disappear the two layers originally present.  On the following day, the solution is neutralized by soda to pH5.  The precipitated oxime is filtered off and washed until SO4(-2) can no longer be detected in significant quantities.  The filtrate and the wash water is shaken 6 times with fresh 25ml quantities of chloroform.  The extract is dried with anhydrous sodium sulfate, filtered and the chloroform is removed under vacuum.  The remaining oxime is added to the main yield and distilled under vacuum.  The yield is about 94%.

Example 2:

Same as Ex. 1, except:  The cyclohexanone is added at 25*C.  (Moderate cooling is necessary to keep the temp below 50*C.) 

Yield is about 93%.

Example 3:

850cc of hydroxylamine sulfonate solution at 17*C is shaken with 42g of cyclopentanone (BP = 125-126*C) until the two layers disappear.  The solution is neutralized by soda to pH5.  The eliminated oxime is filtered and washed until the sulfate ion is no longer present.  The filtrate and the washings are extracted with 6x20ml of fresh ether.  The ether is dried using calcined sodium sulfate.  The ether is removed under vacuum.  USE  A WATER ASPIRATOR!!  The oxime is distilled under reduced pressure at 88-89*C at 11-9mmHg.  The yield is about 96%.

Example 4:

170cc of the hydroxylamine sulfonate solution is shaken with 11.2g of cyclopeptanone until the two layers disappear.  The next day the mix is neutralized with soda to pH5.  The extraction used 5x30ml of ether.  The ether is removed under vacuum. The MP = 23*C and the yield is about 92%.

 
 
 
 
    Aurelius
(Hive Addict)
01-10-03 10:18
No 396996
      GB patent 1062299
(Rated as: excellent)
 Bookmark   

GB 1062299

3,4-dihydroxyphenyl-propane Derivatives


Example 1:

1-(3,4-dihydroxyphenyl)-2-hydroxyaminopropane

To a solution of 144g of protocatechualdehyde in 3L of nitroethane, heated to about 90*C, 14g of ammonium acetate are gradually added, then the mixture is heated at about 100*C for 3 hours.  The excess nitroethane is then distilled off.  The residue is 1-(3,4-dihydroxyphenyl)-2-nitropropene, MP 148-149*C, Yeild 192g : 94%.

Into a mixture of 180g of 1-(3,4-dihydroxyphenyl)-2-nitropropene, 1000ml of methanol, 750 ml of water and about 300ml of 12% aqueous HCl in the presence of 18g of 10% Pd/C, hydrogen is bubbled until absorption practically ceases.  The mixture is filtered and the filtrate is concentrated  to a volume of about 1000ml and extracted with ethyl acetate.  On evaporation of the solvent, 131g (78%) of 3,4-dihydroxybenzyl methyl ketone oxime are obtained, with MP 145-148*C.

A mixture of 36.2g  of 3,4-dihydroxybenzyl methyl ketone oxime, 3.7g of Platinum oxide, 19.5ml of concentrated HCl and 750ml of butanol is hydrogenated at RT until no more hydrogen is taken up.  The mixture is made neutral by the addition of sodium bicarbonate and about 150g of sodium sulfate are added and the mixture is filtered.  To the filtrate, a solution of 11.5g of succinic acid in about 100ml of butanol are added, the solution is concentrated to a volume of about 100ml and cooled.  The succinate of 1.-(3,4-dihydroxyphenyl)-2-hydroxamino-propane precipitates and is collected and dried.  Yield : 27g  MP 157-159*C.  From the succinate, the freebase can be obtained with sodium bicarb solution, extraction with ether and evaporation to yield a product with MP 120-123*C.

Example 2:

1-(3,4-dihydroxyphenyl)-2-methoxaminopropane

A solution of 33.2g of 3,4-dihydroxybenzyl methyl ketone in 300ml of ethanol is admixed with a solution of 16.6g  of O-methylhydroxylamine HCl and 16.4g of sodium acetate in 50ml of water and allowed to stand for 3 days at RT.  The solution is then evaporated to dryness and the residue is taken up and recrystallized from benzene.  Yield: 35g of 3,4-dihydroxybenzyl methyl ketone methoxime, MP: 110-112*C. BP: 140-150*C/0.2mmHg.

A mixture of 30g of the methoxime, 3g of Platinum Oxide, 12.5ml of conc. HCl and 1000ml  of ethanol is hydrogenated as described is Ex. 1.  The mixture is filtered , the filtrate is evaporated to dryness.  The residue is taken up and recrystallized from isopropanol.  Yield: 28.8g (80%) of 1-(3,4-dihydroxyphenyl)-2-methoxaminopropane, MP: 155-158*C.

Example 3:

[b]1-(3,4-dihydroxyphenyl)-2-ethoxaminopropane

A mixture of 13.28g of 3,4-dihydroxybenzyl methyl ketone, 7.76g of N-ethyl hydroxylamine, 6.56g of sodium acetate and 220ml of 90% ethanol is allowed to stand at RT for 2 days, then it is evaporated to dryness.  The residue is taken up in ether, filtered and evaporated to dryness. The residue is again taken up, but this time in benzene from which it is recrystallized and is 3,4-dihydroxybenzyl methyl ketone ethoxime, MP: 126-128*C.

The Ethoxime is hydrogenated by the process described in the foregoing Examples and gives a 76% yield of 1-(3,4-dihydroxyphenyl)-2-ethoxaminopropane, MP: 146-148*C. (recrystallized from isopropanol).

Note:  Any R-group to substituted on the nitrogen may be used, up to and including R-groups of 1-8 carbons.

smile
 
 
 
 
    Aurelius
(Hive Addict)
01-27-03 10:58
No 401914
      US patent 4015011 Preparation of Phenylalkylamines  Bookmark   

US Patent 4015011

Phenylalkylamines and Salts Thereof


Example 1:

1-(3’-formylaminophenyl)-2-aminopropane hydrochloride

1-(m-nitrophenyl)-2-nitropropane (MP: 56-58*C) was prepared by refluxing m-nitrobenzaldehyde and nitroethane in toluene in the presence of benzoic acid and piperidine for 5 hours.  The product was then hydrogenated, first in the presence of palladized charcoal in pyridine at 5 atm and RT and then in the presence of Raney nickel and ammonia in methanol at 5 atm and 40*C. This formed 1-(m-aminophenyl)-2-aminopropane that had; BP: 120-141*C/0.1mmHg; MP: 78-79*C.

3g of the base and 2.32g of maleic acid were dissolved in hot acetonitrile, and upon cooling of the solution the maleate crystallized out.  The maleate has; MP: 131-132*C (from acetonitrile).

255g of the base were dissolved in methanol and the solution was acidified with ethereal HCl acid.  The monohydrochloride was obtained.  The salt was refluxed for 2 hours in 225ml of formic acid and the reaction mixture was then evaporated in a water aspirator vacuum to give a yellow oil which solidified upon being digested in ether.  This crystals were recrystallized from ethanol by addition of ether.  The title compound was thus formed having; MP: 150-153*C.

Example 2:

1-(3’-acetaminophenyl)-2-aminopropane hydrochloride

15g of 1-(3’-aminophenyl)-2-aminopropane were dissolved in glacial acetic acid and ethereal HCl acid was added to the solution.  The salt formed was admixed with 15ml of acetic acid anhydride and the mixture was stirred for 10 minutes at RT.  Thereafter, the reaction mixture was evaporated using a water aspirator whereupon the title compound crystallized out.   The title compound was recrystallized from ethanol to give crystals that had; MP: 181-183*C.

Example 3 used the procedure in Example 2 in an analogous manner to give 1-(3’-acetaminophenyl)-2-methylaminopropane hydrochloride.  The product formed had; MP: 162-165*C

Example 4 used the procedure in Example 2 in an analogous manner to give 1-(3’-acetamidophenyl)-2-ethylaminopropane hydrochloride. The title compound had; MP: 180-182*C

Example 5:

1-[3’-(dimethylaminosulfonylamino)-phenyl]-2-aminopropane  and its maleate

m-nitrobenzyl alcohol was prepared by subjecting m-nitrobenzaldehyde to the cannizaro reaction at 45*C with formalin and potassium hydroxide.  The m-nitrobenzyl alcohol was reacted with thionyl chloride to form its chloride (MP:45*C).  By refluxing the chloride with sodium cyanide in aqueous ethanolic solution for 5 hours in the presence of potassium iodide, m-nitrobenzyl cyanide (MP: 58*C) was formed.  This was hydrolyzed with aqueous HCl to give the m-nitrophenylacetic acid.  The acid thus obtained was then converted into 1-(m-nitrophenyl)-propan-2-one.  (MP: 62*C) using the method from J. Med. Chem. 15, 1174 (1972).  The propanone was reducing with an Iron dissolving-metal reduction that utilized concentrated HCl acid and was stirred an extra 3 hours.  The reduction product was recovered from the reaction mixture by extraction with ether.  Since the product was not distillable without decomposition, it was purified via its oxalate (MP: 127-129*C).  This was prepared by dissolving the base in acetonitrile , adding oxalic acid, filtering, adding aqueous sodium hydroxide and then extracting with ether.  The freebase was liberated from solvent under vacuum. 

13.3g of dimethylsulfochloride was added dropwise to a solution of 11.5g of 1-(3’-aminophenyl)-propan-2-one in 57ml of pyridine at 10-20*C.  The resulting solution was stirred for several hours at RT.  Thereafter,  it was poured into ice water and the aqueous mix was acidified with conc. HCl acid.  Then the mix was extracted with ether and the ether removed under vacuum.  The residue weighed 13.5g.  This compound was hydrogenated with Raney nickel in methanol at 5 atm and 60*C.  the catalyst was removed with filtration, the filtrate evaporated, and the residue taken up in acetonitrile.  The solution was acidified with maleic acid and the precipitate was filtered off.  The maleate had; MP: 128-131*C

Example 6:

1-[3’-(ethoxycarbonylamino)-phenyl]-2-aminopropane hydrochloride

12g of ethyl chloroformate were added dropwise to a solution of 23.9g of 1-(3’-aminophenyl)-propan-2-one oxalate in 150ml of pyridine at 10-20*C and the resulting mixture was first stirred for 6 hours at RT and then allowed to stand at RT for several additional hours.  Thereafter, the reaction mixture was diluted with ice water, acidified with conc. HCl acid, and then extracted with chloroform.  The organic layer was evaporated and the residue vacuum distilled to give 1-[3’-(ethoxycarbonylamino)-phenyl]-propan-2-oneThe ketone had; BP: 170-173*C/0.01mmHg in Yield: 14.5g

This ketone was hydrogenated in methanol using Raney nickel and ammonia at 5 atm and 70-80*C to give the amino propane.  The catalyst was filtered, the filtrated evaporated and the residue dissolved in acetonitrile.  The solution was acidified with ethereal HCl acid and the precipitate filtered. The crystals were recrystallized with acetonitrile with the addition of a small amount of water to give a product that had; MP: 185-186*C.

Example 7:

1-(3’-ureidophenyl)-2-aminopropane and its maleate

15g of 1-(3’-aminophenyl)-propan-2-one were dissolved at 35*C in a mix of 24ml of glacial acetic acid and 48ml of water, and then a solution of 8.1g of potassium cyanate in 45ml of water was added dropwise at 35*C with stirring.  The resulting solution was stirred for 2 hours at RT and was then allowed to stand overnight.  Thereafter, the reaction mixture was diluted with water and extracted with chloroform.  The solvent was evaporated and the residue was recrystallized from ethyl acetate.  The yield was 10g of 1-(3’-ureidophenyl)-propan-2-one that had; MP: 123-124*C.

The ketone was hydrogenated as in Example 6 and the product was purified by chromatography on silica gel.  First methanol/chloroform; 2/8 and then methanol/glacial acetic acid; 49/1 was using as the flow agent.  The eluate evaporated and the residue was admixed with sodium hydroxide and ethyl acetate.  The freebase thereby liberated was dissolved in methanol and the solution was acidified with maleic acid.  Ether was added and the precipitate formed was recrystallized from ethanol/ethyl acetate.  The product had; MP: 139-141*C

Example 8:

1-[3’-(methoxycarbonylamino)-phenyl]-2-aminopropane and its hydrochloride

The respective ketone (MP: 93-95*C) (reprecipitated from isopropanol with pet. ether) was prepared in an analogous manner to Example 6.  The ketone was then hydrogenated as in Example 5.  The catalyst was filtered, and the methanol evaporated.  The residue was dissolved in acetonitrile, and the solution was acidified with ethereal HCl acid.  The precipitate was filtered and recrystallized from acetonitrile.  1-[3’-(methoxycarbonylamino)-phenyl]-2-aminopropane was retrieved having; MP: 185-187*C
 
 
 
 
    Aurelius
(Hive Addict)
01-27-03 11:00
No 401916
      more  Bookmark   

Example 9:

1-[3’-(N’-methylureido)-phenyl]-2-aminopropane and its maleate

2.85g of methylisocyanate were added dropwise to a solution of 7.5g of 1-(3’-aminophenyl)-propan-2-one in 100ml of acetonitrile at RT.  The resulting mix was stirred for 4 hours at 20-25*C while cooling on an ice bath, if needed, then the solvent was distilled off at 20-25*C in vacuo.  The residue was recrystallized from ethyl acetate by addition of pet. ether and the crystals were filtered.  After a wash with ether, the yield was 5.7g of the ketone with; MP: 77-78*C.

The ketone was hydrogenated as in Example 6 and purified as in Example 7.  The free base was liberated from the residue of the evaporated methanol/glacial acetic acid eluate by the addition of sodium hydroxide and DCM.  The base was dissolved in methanol, the solution was acidified with maleic acid and ether was added to precipitate the salt.  The salt had; MP: 128-131*C

Example 10:

1-[3’-(ethylthiocarbonylamino)-phenyl]-2-aminopropane hydrochloride

A mixture of 1-93’-aminophenyl)-2-aminopropane and 12.5ml of ethyl formate was boiled for 10 hours and then the reaction mixture was evaporated, leaving 1-(3’-aminophenyl)-2-(formylamino)-propane.  4.45g of this amide were dissolved in 25ml of pyridine and 2.6ml of chlorothioformic acid-S-ethylester were added to the solution at 10-20*C.  The mixture was allowed to stand for a few hours.  Thereafter, the reaction solution was poured into ice water and the aqueous solution was extracted with ether.  The ether extract was washed 5x with water and 1x with 0.1N HCl acid.  The solution was then evaporated to give 1-[3’-(ethylthiocarbonylamino)-phenyl]-2-(formylamino)-propane.  The residue was added to a mixture of 75ml of methanol and 5ml of conc. HCl acid.  The mixture then stood for 3 days at RT.  Thereafter, the resulting solution was evaporated, the residue was triturated with acetonitrile, and the crystalline product formed was thereby recrystallized from acetonitrile with the addition of water.  The hydrochloride thus yielded had; MP: 185-186*C.

Example 11:

1-(3’-ureidophenyl)-2-methylaminopropane, its oxalate and maleate

7g of 1(3’-ureidophenyl)-propan-2-one were hydrogenated in 70ml of methanol with 8.5ml of methamine in the presence of Raney nickel at 60*C and 5 atm to form 1-(3’-ureidophenyl)-2-methylaminopropane.  Thereafter, the catalyst was filtered, the methanol removed by distillation and the residue was dissolved in methanol. The solution was acidified with oxalic acid giving the oxalate.  The oxalate was dissolved in water, the solution extracted with chloroform and the extract was admixed with sodium hydroxide.  The freebase was extracted with n-butanol.  The butanolic extract was evaporated and the residue taken up in ethanol.  To the ethanolic solution was added a calculated amount of maleic acid.  The precipitate was filtered and dried.  The product (maleate) had; MP: 152-153*C

Example 12:

1-(3’-ureidophenyl)-2-aminopropane maleate

A solution of 22.5g hydroxylamine hydrochloride in 69ml of water was added to a solution of 48g of 1-(3’-ureidophenyl)-propan-2-one.  Then, a solution of 34.5g of sodium carbonate in 87.5ml of water was added dropwise at 50-60*C.  The resulting mix was boiled for 1 hour and then diluted with water, whereupon the oxime crystallized out.  (MP: 152-155*C)  The oxime was collected by filtration and hydrogenated in methanol in the presence of Raney nickel at 60*C and 5 atm to give the aminopropane.  After catalyst had been removed by filtration and the solvent was evaporated from the filtrate, the hydrogenation product was purified by chromatography on a silica gel column.  The flow agent was methanol/glacial acetic acid; 49:1.  The eluate was evaporated, leaving the acetate of the aminopropane.  The freebase was liberated with sodium hydroxide and extracted with n-butanol.  The extract was evaporated and the residue taken up in ethanol.  The solution was acidified with maleic acid to give the maleate, which was precipitated by the addition of ethyl acetate.  The maleate had; MP: 139-141*C

Example 13:

1-(3’-nitrophenyl)-2-aminopropane hydrochloride

A mix of 35.8g of the corresponding propanone, 32ml of formamide and 10.2ml of 98-100% formic acid was heated at 170*C while continuously distilling off the water formed by the reaction.  Carbon dioxide is evolved for about 1 hour of heating, after which the reaction is cooled and poured onto ice water.  The crystals are filtered and reprecipitated from ethyl acetate and pet. ether to give 1-(3’-nitrophenyl)-2-(formylamino)-propane that had; MP: 99-100*C.  

34.5g of this compound were refluxed for 3 hours in 200 ml of conc. HCl acid.  Thereafter, the reaction solution was cooled, diluted with water and extracted with DCM.  The aqueous phase was treated with sodium hydroxide and extracted with DCM.  The organic phase was evaporated and the residue taken up in acetonitrile, the solution was acidified with ethereal HCl acid and the crystals filtered. The crystals were recrystallized from acetonitrile to give the hydrochloride that has; MP: 171-172*C.

Example 14:

1-(3’-ureidophenyl)-2-(aminoacetamido)-propane hydrochloride

A mix of 6.775g of 1-(3’-ureidophenl)-2-aminopropane, 7.315g carbobenzoxyglycine, 4.41g of diisopropylcarbodiimide and 70ml of benzene was refluxed for 2 hours.  Thereafter, the solution was evaporated and the residue was purified by chromatography on a silica gel column.  The flow agent was methanol/chloroform; 2:8.  The eluate was evaporated and the residue was recrystallized from ethyl acetate to give 9.5g of 1-(3’-urediophenyl)-2-(carbobenzoxyamidoacetylamino)-propane that has; MP: 125-130*C.

This was then hydrogenated  in 100 ml of glacial acetic acid in the presence of 1g of Pd/C (5%) at 50*C and 5 atm.  The hydrochloride was prepared by adding 3.1g of benzyl chloride and 50ml of water to the hydrogenation mixture and again hydrogenated until H2 ceased.  Thereafter, the catalyst was filtered, the solvent evaporated and the residue was crystallized with acetonitrile. The crystals were then recrystallized from methanol to give the product that has; MP: 212-215*C

Example 15:

1-(3’-ureidophenyl)-2-formylaminopropane

A mix of 4.8g of 1-(3’-ureidophenyl)-2-aminopropane and 5ml of ethyl formate was refluxed for 5 hours.  Then the reaction solution was evaporated to give a residue that was purified by silica gel column chromatography.  The flow agent was methanol/chloroform; 2:8.  The eluate was evaporated and the residue was recrystallized from ethanol and ether.  The product had; MP: 133-136*C.

Example 16:

1-(3’-ureidophenyl)-2-(cyanomethylamino)-propane maleate

A mix of 4.8g of 1-(3’-ureidophenyl)-2-aminopropane, 3.5g of potassium carbonate, 1.6ml of chloroacetonitrile and 50ml of acetonitrile was refluxed for 2 hours.  Thereafter, the inorganic precipitate was filtered.  The solvent was evaporated and the residue was purified using silica gel column chromatography.  The flow agent was methanol/chloroform; 2:8.  the eluate was evaporated and the residue was dissolved in acetonitrile to which maleic acid was added in a calculated amount.  The crystals were filtered.  The product had; MP: 129-131*C (w/decomp.)

 
 
 
 
    Aurelius
(Hive Addict)
01-27-03 11:00
No 401917
      more  Bookmark   

Example 17:

1-(3’-aminophenyl)-2-(phenacylamino)-propane

A mixture of 9.6g of 1-(3’-acetaminophenyl)-2-aminopropane (Example 2), 10g of alpha-bromoacetophenone, 7g of potassium carbonate and 200ml of acetonitrile was refluxed for 3 hours.  Thereafter, the inorganic precipitate which had formed was removed by filtering and 5g of oxalic acid was added to the filtrate. The precipitate was filtered giving 6g of 1-(3’-acetamidophenyl)-2-(phenacylamino)-propane oxalate that has; MP: 136-140*C

The oxalate was added to 60ml of ethanolic 10% hydrochloric acid and the mix was refluxed for 4 hours.  The solvent was evaporated, the residue was crystallized by the addition of acetonitrile and a small amount of water.  The product was dissolved in water, filtering through activated charcoal and then adding acetonitrile to the filtrate.  The dihydrochloride has; MP: 169-173*C

Example 18:

1-(3’-aminophenyl)-2-(benzylaminoacetyl)-propane dihydrochloride

7.5g of chloroacetyl chloride were added dropwise to a mix of 18g of 1-(3’-nitrophenyl)-2-aminopropane, 14g of potassium carbonate and 150ml of acetonitrile, whereby the temperature of the mixture rose to 45*C and the resulting mix was refluxed for 2 hours.  Thereafter, the mix was allowed to cool and then it was diluted with ice water. The crystals were recrystallized from ethyl acetate and pet.  ether.   1-(3’-nitrophenyl)-2-(chloroacetylamino)-propane crystallized out.  It has; MP: 118-120*C

17g of this compound were added to a mix of 14g benzylamine an 200ml of acetonitrile and the mix was refluxed for 2hours.  Thereafter, the benzylamine hydrochloride was filtered off, the filtrate was acidified with ethereal HCl acid and a precipitate formed.  These were recrystallized from 1.0N HCl acid to give 11.5g of 1-(3’-nitrophenyl)-2-(benzylaminoacetylamino)-propane hydrochloride that had; MP: 167-170*C

This compound was hydrogenated in the presence of Raney nickel at 1 atm and RT.  This gave 1-(3’-aminophenyl)-2-(benzylaminoacetylamino)-propane hydrochloride which dissolved in ethanol  and the solution was admixed with the calculated amount of ethereal HCl to give the dihydrochloride.  The dihydrochloride had; MP: 234-236*C

Example 19:

1-(3’-aminophenyl)-2-(aminoacetylamino)-propane hydrochloride

6g of the dihydrochloride obtained in Example 18 were debenzylated by hydrogenation in 60ml of methanol in the presence of 0.5g of Pd/C  at 60*C and 5 atm.  The catalyst is removed by filtration, the solvent evaporated and the residue taken up in ethanol.  The product is recrystallized by ethanol and acetonitrile to give the title compound.  The title compound has; MP: 195-197*C.

Example 20:

1-(3’-aminophenyl)-2-(methoxycarbonylamino)-propane maleate

5.33ml of methyl chloroformate were added dropwise to a mix of 12.6g of 1-(3’-nitrophenyl)-2-aminopropane, 9.8g of potassium carbonate and 100ml of acetonitrile, whereby the temperature of the mix rose to 45*C.  The resulting mix was boiled for 2 hours.  Thereafter, the reaction mix was diluted with water and dried to give 11g of 1-(3’-nitrophenyl)-2-(methoxycarbonylamino)-propane that had; MP: 104-105*C

This compound was hydrogenated using Raney nickel at 1 atm in methanol at RT.  Thereafter, the catalyst was filtered, the methanol distilled and the residue was dissolved in acetonitrile.  Maleic acid was added in the calculated amount and the crystals were filtered.  Upon double recrystallization from acetonitrile, the product had; MP: 125-127*C; Yield: 5.5g

Example 21:

1-(3’-aminophenyl)-2-formylaminopropane

5.2g of 1-(3’-nitrophenyl)-2-formylaminopropane was hydrogenated with Raney nickel at RT and 1 atm in methanol.  Thereafter, the catalyst was filtered and the solvent was evaporated.  The residue was purified on silica gel using methanol/ chloroform; 2:8 for the flow agent.  The eluate was evaporated and the residue collected was recrystallized from ethyl acetate.  The title compound had; MP: 107-108*C.

Further information in the patent described the compounding of these substances with other inert materials for use in hypertensive preparations.


 
 
 
 
    Rhodium
(Chief Bee)
01-27-03 11:24
No 401927
      Summary/description please!  Bookmark   

Aurelius: Could you please add one or two lines of summary at the top of each patent transcription you make, so that one don't have to meticulously read through the entire posts to see what they are doing in each patent?
 
 
 
 
    Aurelius
(Hive Addict)
01-27-03 20:34
No 402047
      sure  Bookmark   

sure.
 
 
 
 
    Aurelius
(Hive Addict)
01-30-03 14:16
No 402776
      US patent 4707294 Preparation of NH2OH and salts
(Rated as: excellent)
 Bookmark   

US Patent 4707294

Preparation of alcoholic Hydroxylamine Solution from Hydroxylammonium Sulfate


Abstract:

Solid hydroxylammonium sulfate is reacted with an alcohol solution of an alkali metal hydroxide or alkoxide to produce an alcoholic hydroxylamine liquid phase and a sulfate-containing solid phase.  The liquid phase may be used for further reactions such as oxidations, hydroxamic acid production or neutralization to other hydroxylammonium salts.  The different bases behave differently with regard to suitable and preferable solvents and temperatures.


Notes on Reactants:

The concentration of the NaOH in methanol or ethanol is not critical, but it is preferred to operate as near to the solubility limit as possible without creating so viscous a solution as to make the agitation difficult. 

NaOH in ethanol should be used at 10*C (no higher than 30*C, preferably below 20*C).

KOH in methanol IS NOT SUITABLE for this reaction.  Extremely low yields result.  However, KOH in ethanol is VERY suitable.


Example 1:

Hydroxylamine Freebase

A solution of methanolic NaOH was prepared by mixing NaOH (17.2g, 0.43mol) with absolute methanol (150ml) in a 250ml flask.

In the meantime, a 500ml, 3-neck flask was fitted with a thermometer, dropping funnel and N2 inlet (inert atmosphere) and a mag. stirrer.  Solid hydroxylamine sulfate (35g, 0.213mol) was placed in the flask with methanol (50ml) and the flask was placed in an ice-water bath over a stir plate.  With vigorous stirring, the methanolic NaOH solution was added slowly (over 5 minutes) using the dropping funnel while keeping the reaction temperature below 10*C.  After the addition was complete, stirring was continued for 1.5 hours with cooing (5-10*C).  A white slurry formed and was filtered.  The cake was washed with 25ml of methanol.  The clear, colorless filtrate (pH 12.5) was analyzed for free hydroxylamine by mixing with known excess of MEK (40g) and adjusting the pH to 7 with conc. H2SO4 (2.5g).  Methyl ethyl ketoxime formed was determined by GC to correspond to free hydroxylamine.  Yield: 87.4%

The white filter cake (34.2g) of sodium sulfate by dissolving in water (150ml) and mixing the excess of MEK (40g) and titrating with 50% NaOH solution (3.9g) to pH 7.  The amount of hydroxylamine sulfate left in the cake represented 11.4% of the total.

Example 8:

Hydroxylamine freebase

The experiment was conducted using the same equipment as Example 1.  Sodium hydroxide (17.2g, 0.43mol) was dissolved in methanol (200ml) and the solution was placed in the 500 ml flask.  With stirring and cooling (5-10*C) solid hydroxylamine sulfate was added using a spatula over 20 minutes.  The mixture was then stirred for 1.5 hours more and the white slurry was filtered. 

The filtrate on analysis in the usual manner showed 86.6% of the hydroxylamine.  The solid on analysis was found to contain 10.4% of hydroxylamine sulfate that was started with.

Example 11:

Hydroxylamine freebase

Sodium hydroxide pellets (17.2g, 0.43mol) were stirred over nearly two hours in a 500ml flask with absolute ethanol (200ml) till a clear solution was obtained.  The solution was placed in a 250ml, 3-neck flask fitted with thermometer and a drying tube (Drierite TM was used).  A stirring rod was placed in the solution along with hydroxylamine sulfate (35g, 0.213mol) and absolute ethanol (20ml).  As the contents were stirring vigorously over the stir-plate with cooling in an ice-water bath (5-10*C), the ethanolic NaOH was added slowly over 10 minutes.  The slurry was filtered and the cake washed with 25ml of absolute ethanol. 

The white cake (38.6g) was analyzed in the usual manner and was found to contain hydroxylamine sulfate as 4.7% of the mass.   The clear filtrate was analyzed by GC after mixing with excess MEK (40g) and adjusting the pH to 7 with conc. Sulfuric acid.  Yield: 88.3%

Example 26:

Hydroxylamine Nitrate

A solution of sodium methoxide in methanol produced by dissolving sodium (10g, 0.435mol) in methanol (150ml) was stirred with hydroxylamine sulfate (35g, 0.213mol) in an ice-water bath (5-10*C) for more than 2 hours.  The slurry was filtered and the clear methanolic filtrate with cake-wash (pH 9.2) was mixed with conc. Sulfuric acid (0.8g) to pH 8.0.  The thin white solid produced was filtered off and the clear filtrate was placed in a 500ml flask with a mag. stirrer.  While cooling in ice-water and stirring, conc.  Nitric acid (35.5g) was added til the pH was 2.8.  The clear methanolic solution of hydroxylamine nitrate (273.3ml) was found to contain 37.99g of the nitrate (13.9g/100ml).  Yield: 92.7%

Example 27:

Hydroxylamine Phosphate:

A solution of hydroxylamine sulfate (210g, 1.28mol) in methanol (228ml) at a concentration of 4.84g/100ml.  The solution was placed into a 250ml 3-neck flask with a thermometer, stirrer and a dropping funnel.  While stirring above an ice-water bath (5*C), 85% orthophosphoric acid (8.0g, 0.069mol) was added slowly til the pH of the solution went from 11.8 to 8.0.  A white slurry is produced.  Stirring at 5*C was continued for 15minutes more.  Then, the solution was filtered and the solid weighed 11.8g.  this was recrystallized from hot water the phosphate was collected.  Yield: 85.4% that had; MP: 175*C

Example 28:

Hydroxylamine Oxalate

A solution of hydroxylamine in methanol (680ml) as in Example 27 was used (pH 11.8).  Conc.  Sulfuric acid was added slowly to adjust the pH to 8.0 and the thin white precipitate formed was filtered off and the clear filtrate placed in a 1L flask with mag stirring.  The flask was placed on an ice bath (5*C) and oxalic acid (45g, 0.5mol) was added dissolved in methanol (100Mml) slowly with cooling and stirring.  The thick white slurry thus produced was filtered to give 84.8g of cake.  The cake was recrystallized from hot water to give the oxalate in 94.6% yield.  It had; MP: 192*C (with decomp.)

Example 29:

Hydroxylamine Freebase

A 500ml, 3-neck flask was fitted with a thermometer, reflux-condensor and drying tube. Freshly cut sodium (10g, 0.435mol) was placed in the flask and absolute methanol (175ml) was carefully added with cooling.  After the sodium was completely dissolved in methanol forming a clear solution of sodium methoxide, solid hydroxylamine sulfate (35g, 0.213mol) was added over 2 minutes.  No significant heat was evolved.  The mix was stirred with cooling (10*C) in ice-water bath with mag stirring for 1 hour.  Subsequently, cooling was removed and vigorous stirring continued for 2 hours.   By this point a slurry had formed and this was filtered and the cake washed using more methanol.  The total filtrate (162g) was analyzed potentiometrically and found to contain hydroxylamine corresponding to 87.5% yield.  The filtrate was virtually water-free.  Unused  hydroxylamine sulfate amounted to 1.6%.

References Cited:

US Patent 4551323

USSR 168305




 
 
 
 
    Aurelius
(Hive Addict)
01-31-03 10:40
No 403017
      US Patent 6235935 Preparation of Oximes  Bookmark   

US Patent 6235935

Method of Manufacturing High Purity Oximes from Aqueous Hydroxylamine and Ketones


Abstract:

High purity oximes are prepared from aqueous hydroxylamine and ketones reacted at ambient temperature without addition of impurities such as salts or acids.

Example 1:

Acetone Oxime

50ml of high purity acetone was added to 100ml of high purity 50% hydroxylamine/50% water (by weight), and stirred magnetically.  The mix was left to  reach equilibrium by sitting a few hours to reach ambient temperature.  50ml of 98% formic acid in water was then added to the mixture to give a pH of 6.0-6.2 and mixed to reach equilibrium.  The crystalline product was filtered.  The mix was left to stir for another 24 hours.  The formed crystals were filtered and added to those already collected. 

Purification proceeded as follows: 
The crystals were dissolved in a non-polar solvent (perfluorocyclohexane) by heating and cooled overnight at RT to recrystallize.  The material was then filtered and washed with the solvent.  The oxime had; MP: 61-63*C; Yield: 85-90%.

Notes of the Reaction:

Other acids may be used to adjust the pH to 6.0-6.2.  However, with inorganic acids, ionic impurities may be added. 


Acid      %Yield
H2       87.5
HNO3      835
HCl          76.7
Acetic      78.6
Citric        78.6


Example 2:

Acetyl Acetone Dioxime

50ml of high purity acetyl acetone was gradually added to 100ml of high purity 50%hydroxylamine/50%water in a glass beaker and stirred with a magnetic stirrer overnight at RT.  The product separated as crystals.  They were purified as in Example 1.  Yield: 1.54g (83%); MP: 140-144*C

Example 3:

Cyclohexanone Oxime

50ml of high purity cyclohexanone was gradually added to 100ml of high purity 50%hydroxylamine/50%water in a glass beaker and stirred overnight at RT.  The oxime separated as crystals.  Yield: 1.55g (95%), MP: 86-90*C

References Cited:

US Patents:
3429920
3941840
4128579
4929756
5117060
5254734
5300689
5488161

Other References:

CA 127:81069 (1997)