AU766255B2 - Improved process for phosphorylation and compounds produced by this process - Google Patents
Improved process for phosphorylation and compounds produced by this process Download PDFInfo
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- AU766255B2 AU766255B2 AU43870/00A AU4387000A AU766255B2 AU 766255 B2 AU766255 B2 AU 766255B2 AU 43870/00 A AU43870/00 A AU 43870/00A AU 4387000 A AU4387000 A AU 4387000A AU 766255 B2 AU766255 B2 AU 766255B2
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/582—Recycling of unreacted starting or intermediate materials
Description
PCT/AU00/00452 Received 22 January 2001 Improved Process For Phosphorylation And Compounds Produced By This Process Field of the invention The invention relates to an improved process for phosphorylation of organic hydroxyl groups and the compounds produced using this process.
Background of the invention In this specification, where a document, act or item of knowledge is referred to or discussed, this reference or discussion is not to be taken as an admission that the document, act or item of knowledge or any combination thereof was at the priority date: part of common general knowledge; or known to be relevant to an attempt to solve any problem with which this specification is concerned.
Whilst the following discussion highlights the invention with respect to dietary supplements, it is believed that the same principles apply to other compounds containing organic hydroxyl groups such as pharmaceutical compounds with hydroxyl groups.
The use of dietary supplements is well known, for example hormones, phytosterols or chromans. One of the problems encountered with such supplements for human ingestion is that many of the supplements are relatively water insoluble but the human digestive tract is a substantially aqueous system. Previous attempts to overcome this problem include using emulsifiers to enable an oil-based solution of the supplement to combine with an aqueous system and thus maintain the supplement's bioavailability. Consequently, it would be useful to be able to convert these dietary supplements to water soluble compounds without disturbing their inherent structure. Phosphate salts with either potassium or sodium are already found in biological tissue. Therefore phosphate salts should be tolerated by the body.
There is a diverse art for the production of organic phosphates, however none of these methods are considered to be suitable for production of complex phosphate compounds because they are either unsuitable for use on a commercial scale or there are side reactions which produce undesired by-products.
AMENDED SHEET
IPEAUL
PCT/AU00/00452 Received 22 January 2001 la Ordinarily, phosphorylation reagents and methods are chosen to avoid significant degradation of the compound being phosphorylated. Where gentle conditions are required, then reagents such as 2:2:2-trichloroethyl dichlorophosphate, di-imidazolide chlorophosphate and di-analide chlorophosphate have been employed but have limited yields which are inadequate for commercial processes. When more severe conditions are feasible, then phosphorous oxychloride has been used, but the reaction produces a variety of by-products together with hydrogen chloride. There are other problems associated with
IAENAU
PCT/AU00/00452 Received 15 March 2001 2 the fact that phosphorous oxychloride is difficult to manage which make this reagent unsuitable for use on a commercial scale.
Although P 4 0 1 0 [which is often incorrectly called phosphorous pentoxide] has been used for phosphorylation of ethanol and other short chain primary alcohols, it has not been used for higher alcohols and complex molecules because the temperatures used are too high and there is considerable degradation. Another reason why P 4 0 10 is not used for higher alcohols and complex molecules is that at the higher temperatures used in known P 4 010 processes, there is formation of a significant amount of by-products. Even with ethanol, there is a significant amount of diethylphosphate as well as monoalkylphosphate which is produced and these substances must be removed. Commercial processes use P 4 0 10 with ethanol but there is a complicated clean-up procedure because the reaction occurs at a high temperature.
Further, with secondary or tertiary alcohols P 4 0 1 0 causes dehydration and formation of a double bond. This dehydration is further promoted by the high temperatures at which this reaction takes place. In fact, this is a standard reagent and method for forming a double bond. This reaction has thus been considered to be unsuitable for production of complex phosphate compounds.
It is the need for lower temperatures which has led to the use of POC13 because, in the presence of a base, a lower temperature can be used and degradation is avoided. POC13 is the preferred method for phosphorylating complex molecules.
There is, therefore, a need for a reliable process for phosphorylating complex compounds so that these compounds can be used in aqueous environments.
Summary of the invention It has surprisingly been found that P 4 0 1 0 can be used to phosphorylate primary fatty alcohols, secondary alcohols (including cyclohexanols) and aromatic alcohols (including phenols and chromanols). In this description and in the claims, the term "complex alcohols" refers to primary fatty alcohols, secondary alcohols and aromatic alcohols.
The complex alcohols include hormones, phytosterols, tocopherols (chromans), vitamin K1 and other oil-soluble vitamins and dietary supplements as well as pharmaceutical compounds such as Amoxycillin.
AMENDED SHEET
IPEA/AU
10847581 PCT/AU00/00452 Received 15 March 2001 3 In this description, the word "intimate" is used to signify its technical meaning as known to persons skilled in the art. That is, to signify that two substances are in very close physical contact dispersed as particles which are as small as possible so that a reaction is initiated.
There must be as large a surface area as possible for the reaction to initiate and this is also advantageous for further reaction.
Accordingly, there is provided a process for phosphorylating complex alcohols comprising the following steps: forming an intimate mixture of one or more complex alcohols and P 4 0 10 at a temperature below 80'C in the absence of additional solvents; and allowing the intimate mixture to continue to react for a period of time at a temperature below 80 0 C until the formation of the dihydrogen form of the phosphorylated complex alcohol is substantially completed.
It is understood that in steps and the temperature is sufficient to ensure there is minimum degradation of the complex alcohols but the reaction will still proceed to a satisfactory extent.
The complex alcohols must be in a liquid phase at the desired temperature of reaction.
Persons skilled in the art will be aware that some complex alcohols are commercially supplied in a stabilizing medium. Such complex alcohols, may be used in this process without removing the stabilizing medium.
Preferably, where minimum degradation is desired, the temperature at which the reaction is performed is in the range from 0 to 50 0 C. More preferably, the temperature is in the range from 0 to Preferably where the period of time in step is minimized, the temperature at which the reaction is performed is about The ratio of P 4 0 10 to complex alcohols will depend on the temperature at which the reaction occurs. At the higher temperatures, the ratio of phosphorus to complex alcohols is substantially equimolar. That is, at the higher temperatures there is more efficient consumption of the phosphate groups. At the lower temperatures, the ratio of P 4 0 1 0 to complex alcohols is substantially equimolar.
AMENDED
SHEET
IPEV/A
U
PCT/AU00/00452 Received 15 March 2001 4 The period of time in step is dependent on the temperature at the ratio of reagents.
Where there is equimolar phosphorus, preferably the period of time does not exceed about minutes. Where there is equimolar P 4 0 10 preferably the period of time does not exceed about 10 minutes.
s The choice of temperature at which the reaction occurs is dependent on the expense of the complex alcohols. For example, Amoxycillin is expensive therefore it is preferable to minimize the degradation of Amoxycillin.
Where lower temperatures are used and there are unreacted reagents, the unreacted reagents can be recycled. For example, if the temperature is between 0 to 40 0 C, the process would further comprise a step where the unreacted reagents were mixed with more
P
4 0 1 0 and complex alcohol and steps and repeated.
The phosphorylated complex alcohols may be recovered as either the acid or as a salt (usually potassium or sodium) using methods known to those skilled in the art. For example, the reaction mixture from step may be neutralized with potassium or sodium hydroxide then the water evaporated to recover the salt.
The pressure is typically at atmospheric because there is no advantage using higher pressures at these temperatures.
The intimate mixture is formed using methods known to those skilled in the art. Vigorous stirring is typically necessary to achieve an intimate mixture. In a laboratory, a mortar and pestle can be used. In an industrial plant, a high shear mixer would be used.
According to a preferred embodiment, formation of the intimate mixture in step is performed in the presence of an aliphatic carboxylic acid excluding formic and acetic acid.
In this description and in the claims, the term "aliphatic acid" refers to any aliphatic carboxylic acid except for formic acid and acetic acid. Preferably, the aliphatic acid is a free fatty acid. Examples include oleic acid and stearic acid. The aliphatic acid acts as a catalyst for the reaction and reduces the side reactions.
AMENDED SHEET
!PEAU
WO 00/69865 PCT/AU00/00452 According to another form of the invention, there is provided a phosphate derivative of a complex alcohol which was produced by the above process.
Examples The invention will now be further explained and illustrated by reference to the following non-limiting examples.
Example 1
P
4 0 1 0 (0.28 g) was added to 1-dodecanol (0.18 g) and stearic acid (0.02g). The mixture was stirred vigorously for 5 mins at 20-25 0 C. The product was analyzed by electrospray mass spectrometry which showed the formation of 1-dodecanol phosphate.
Example 2 A phytosterol extract containing mainly beta sitosterol, stimasterol and campastenol (0.4g) was mixed with polyphosphoric acid (0.8g) at 20-250C by grinding in a mortar and pestle for 0.5 hours then let stand for 12 hours at ambient temperature. The product was diluted with acetonitrile and then analyzed by spray mass spectrometry which showed that the mono-phosphates of the sterols were present.
Example 3 17 beta-estradiol (0.27g) was mixed with polyphosphoric acid (0.3g) at 20-25 0 C in a mortar and pestle for 0.5 hours then let stand for 12 hours at ambient temperature. The product was diluted with acetonitrile and analyzed by spray mass spectrometry which showed that 17 beta-estradiol monophosphate had been formed.
Example 4 Alpha-phylloquinone (or vitamin K1) (0.45g in 5g oleic acid) was mixed with P 4 0 0 i at 0 C in a mortar and pestle for 0.5 hours then let stand for 12 hours at ambient temperature. The product was analyzed which showed that the mono-phosphate was formed.
WO 00/69865 PCT/AU00/00452 6 Example
P
4 0 1 0 (165.lg) was added to tocopherol (1 kg) and stirred together for 30 minutes at 70 0
C.
The mixture discoloured to give a brown/black material which became very viscous. The material was then mixed vigorously with a mechanical stirrer for 30 minutes in water (10 1) to form a slurry. The slurry was then centrifuged, the water discarded, and the pellet collected. The pellet was then dissolved in AR ethanol (10 Then sodium (160.4 g) was added slowly to the solution and stirred by a magnetic stirrer. The mixture was then filtered, resuspended in AR ethanol (10 1) and heated to reflux, so dissolving the unreacted tocopherol and fatty acid. The hot dispersion was cooled and filtered to recover di-sodium tocopherol phosphate.
Example 6
P
4 0 10 (3.0g)was added to a mixture of dopamine hydrochloride (2.0g) and stearic acid (0.04g), then mixed together. To the resulting heterogenous solid was added water (0.3-0.5 ml), causing an exothermic reaction (-50 0 The resulting slurry was stirred for 2-3 minutes, then water (50 ml) was added completely dissolving the mixture. The mixture was analyzed using electro-spray mass spectrometry to find dopamine phosphate and inorganic phosphates.
Example 7 The above procedure (example 6) was repeated with amoxicillintrihydrate stearic acid (0.04g) and P 4 0o 0 The product mixture contained Amoxicillin phosphate and inorganic phosphates.
Example 8 The above procedure (example 6) was repeated with cholesterol stearic acid (0.04g) and P 4 0 10 The reaction mixture was dispersed into water (50 ml) then centrifuged to recover the cholesterol phase. This phase was analyzed and was found to contain unreacted cholesterol and cholesterol phosphate.
The novel process for phosphorylation has been successfully used for a variety of useful compounds and would be understood by those skilled in this art to have an obviously wider application.
I__I
WO 00/69865 PCT/AU00/00452 7 The word 'comprising' and forms of the word 'comprising' as used in this description and in the claims does not limit the invention claimed to exclude any variants or additions.
Modifications and improvements to the invention will be readily apparent to those skilled in the art. Such modifications and improvements are intended to be within the scope of this invention.
Claims (9)
1. A process for phosphorylating complex alcohols comprising the following steps: forming an intimate mixture of one or more complex alcohols and P 4 0 1 0 at a temperature below 80'C in the absence of additional solvents; and allowing the intimate mixture to continue to react for a period of time at a temperature below 80'C until the formation of the dihydrogen form of the phosphorylated complex alcohol is substantially completed.
2. A process according to claim 1 wherein the temperature in steps and is in the range from 0 to
3. A process according to claim 2 wherein the temperature in steps and is in the range from 0 to 40 0 C.
4. A process according to claim 1 wherein the temperature in steps and is about 0 C. A process according to any one of claims 1 or 4 wherein the ratio of phosphorus to complex alcohols is substantially equimolar.
6. A process according to any one of claims 2 or 3 wherein the ratio of P 4 0 1 to complex alcohols is substantially equimolar.
7. A process according to claim 5 wherein the period of time in step does not exceed about 30 minutes.
8. A process according to claim 6 wherein the period of time in step does not exceed about 10 minutes.
9. A process according to any one of the preceding claims wherein the intimate mixture in step is formed in the presence of an aliphatic acid. A process according to claim 9 wherein the aliphatic acid is a free fatty acid.
11. A phosphate derivate of a complex alcohol which was produced according to any one of the above claims. AMENDED SHEET FPEA/AU
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU43870/00A AU766255B2 (en) | 1999-01-25 | 2000-05-12 | Improved process for phosphorylation and compounds produced by this process |
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AUPP8293A AUPP829399A0 (en) | 1999-01-25 | 1999-01-25 | Recovery for chroman derivatives |
AUPQ0374A AUPQ037499A0 (en) | 1999-05-14 | 1999-05-14 | Improved process for phosphorylation and compounds produced by this method |
AUPQ0374 | 1999-05-14 | ||
AU26465/00 | 2000-01-25 | ||
PCT/AU2000/000038 WO2000043380A1 (en) | 1999-01-25 | 2000-01-25 | Recovery of chroman derivatives |
PCT/AU2000/000452 WO2000069865A1 (en) | 1999-05-14 | 2000-05-12 | Improved process for phosphorylation and compounds produced by this process |
AU43870/00A AU766255B2 (en) | 1999-01-25 | 2000-05-12 | Improved process for phosphorylation and compounds produced by this process |
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AU4387000A AU4387000A (en) | 2000-12-05 |
AU766255B2 true AU766255B2 (en) | 2003-10-09 |
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AU43870/00A Expired AU766255B2 (en) | 1999-01-25 | 2000-05-12 | Improved process for phosphorylation and compounds produced by this process |
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Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
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AU2003901812A0 (en) * | 2003-04-15 | 2003-05-01 | Vital Health Sciences Pty Ltd | Phosphates of secondary alcohols |
AU2003301765B2 (en) * | 2003-04-15 | 2005-11-24 | Vital Health Sciences Pty Ltd | Phosphates of secondary alcohols |
BR112019012946A2 (en) | 2016-12-21 | 2019-11-26 | Avecho Biotechnology Ltd | process |
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PC1 | Assignment before grant (sect. 113) |
Owner name: VITAL HEALTH SCIENCES PTY LTD Free format text: THE FORMER OWNER WAS: SWIG PTY LTD |
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FGA | Letters patent sealed or granted (standard patent) | ||
GD | Licence registered |
Name of requester: ISP INVESTMENTS LLC |
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MK14 | Patent ceased section 143(a) (annual fees not paid) or expired |