AU2002352672A1 - Novel benzoylecgonine compositions and methods for producing them - Google Patents
Novel benzoylecgonine compositions and methods for producing themInfo
- Publication number
- AU2002352672A1 AU2002352672A1 AU2002352672A AU2002352672A AU2002352672A1 AU 2002352672 A1 AU2002352672 A1 AU 2002352672A1 AU 2002352672 A AU2002352672 A AU 2002352672A AU 2002352672 A AU2002352672 A AU 2002352672A AU 2002352672 A1 AU2002352672 A1 AU 2002352672A1
- Authority
- AU
- Australia
- Prior art keywords
- benzoylecgonine
- water
- hydroxypropyl
- reaction
- esters
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 239000000203 mixture Substances 0.000 title claims description 42
- 238000000034 method Methods 0.000 title claims description 34
- KZFBHCCLJSAHBQ-UHFFFAOYSA-N Benzoylecgonine Natural products CN1C2CCC1C(C(C2)OC(=C)c3ccccc3)C(=O)O KZFBHCCLJSAHBQ-UHFFFAOYSA-N 0.000 title claims description 26
- GVGYEFKIHJTNQZ-RFQIPJPRSA-N ecgonine benzoate Chemical compound O([C@@H]1[C@@H]([C@H]2CC[C@@H](C1)N2C)C(O)=O)C(=O)C1=CC=CC=C1 GVGYEFKIHJTNQZ-RFQIPJPRSA-N 0.000 title claims description 26
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 claims description 64
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 52
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 42
- -1 2- hydroxypropyl benzoylecgonine esters Chemical class 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 34
- 229960003920 cocaine Drugs 0.000 claims description 30
- 239000011541 reaction mixture Substances 0.000 claims description 18
- HZGRVVUQEIBCMS-HTRCEHHLSA-N (1s,5r)-8-methyl-8-azabicyclo[3.2.1]oct-3-ene-4-carboxylic acid Chemical compound C1C=C(C(O)=O)[C@H]2CC[C@@H]1N2C HZGRVVUQEIBCMS-HTRCEHHLSA-N 0.000 claims description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 6
- 239000011261 inert gas Substances 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 229910052786 argon Inorganic materials 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 description 8
- PHMBVCPLDPDESM-YWIQKCBGSA-N Ecgonine Natural products C1[C@H](O)[C@@H](C(O)=O)[C@H]2CC[C@@H]1N2C PHMBVCPLDPDESM-YWIQKCBGSA-N 0.000 description 7
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 7
- PHMBVCPLDPDESM-UHFFFAOYSA-N d-Pseudoekgonin Natural products C1C(O)C(C(O)=O)C2CCC1N2C PHMBVCPLDPDESM-UHFFFAOYSA-N 0.000 description 7
- PHMBVCPLDPDESM-FKSUSPILSA-N ecgonine Chemical compound C1[C@H](O)[C@H](C(O)=O)[C@H]2CC[C@@H]1N2C PHMBVCPLDPDESM-FKSUSPILSA-N 0.000 description 7
- 239000012467 final product Substances 0.000 description 6
- 239000011521 glass Substances 0.000 description 5
- 239000002585 base Substances 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 239000005711 Benzoic acid Substances 0.000 description 3
- 235000010233 benzoic acid Nutrition 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 229930013930 alkaloid Natural products 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- 238000012430 stability testing Methods 0.000 description 2
- 238000005809 transesterification reaction Methods 0.000 description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- 230000037374 absorbed through the skin Effects 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 230000008238 biochemical pathway Effects 0.000 description 1
- 150000005829 chemical entities Chemical class 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 208000037765 diseases and disorders Diseases 0.000 description 1
- QIQNNBXHAYSQRY-UYXSQOIJSA-N ecgonine methyl ester Chemical compound C1[C@H](O)[C@H](C(=O)OC)[C@H]2CC[C@@H]1N2C QIQNNBXHAYSQRY-UYXSQOIJSA-N 0.000 description 1
- QIQNNBXHAYSQRY-UHFFFAOYSA-N ecgonine methyl ester Natural products C1C(O)C(C(=O)OC)C2CCC1N2C QIQNNBXHAYSQRY-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 210000003780 hair follicle Anatomy 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000002634 lipophilic molecules Chemical class 0.000 description 1
- QIGOZTHDQZFDPY-UHFFFAOYSA-L magnesium;sulfate;trihydrate Chemical compound O.O.O.[Mg+2].[O-]S([O-])(=O)=O QIGOZTHDQZFDPY-UHFFFAOYSA-L 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- ZPUCINDJVBIVPJ-XGUBFFRZSA-N methyl (1s,3s,4s,5r)-3-benzoyloxy-8-methyl-8-azabicyclo[3.2.1]octane-4-carboxylate Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-XGUBFFRZSA-N 0.000 description 1
- ZPUCINDJVBIVPJ-UHFFFAOYSA-N methyl 3-benzoyloxy-8-methyl-8-azabicyclo[3.2.1]octane-4-carboxylate Chemical compound COC(=O)C1C(N2C)CCC2CC1OC(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 210000002374 sebum Anatomy 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
Description
NOVEL BENZOYLECGONINE COMPOSITIONS AND METHODS FOR PRODUCING THEM
TECHNICAL FIELD This invention relates to novel compositions comprising benzoylecgonine and structurally related compounds, and methods for producing them.
BACKGROUND
Compositions comprising benzoylecgonine and structurally-related chemical compounds (such as ecgonine, ecgonidine and derivative thereof) are useful in preventing and treating a number of important diseases and disorders (see, for example, US patents 4,469,700; 4,512,996; 4,556,663; 5,376,667; 5,559,123 and 5,663,345; each of which is hereby incorporated herein in its entirety). Particularly useful benzoylecgonine-related compounds include the 2-hydroxypropyl ester derivatives of benzoylecgomne, ecgonine, and ecgomdine. Methods for producing compositions comprising these 2-hydroxypropyl esters have been described in US patent 5,376,667. The preferred method described in US patent 5,376,667 utilizes the step of heating cocaine base in a propylene glycol/water solution (95% propylene glycol/5% water w/w) at 50°C for 12 days, after which time less than 0.1% of the cocaine base starting material remained (see column 7, lines 3- 17). The composition produced by this method comprises approximately 5% w/w of an active component mixture in propylene glycol, wherein the active component mixture comprises approximately 65% benzoylecgonine, 2% ecgonidine and 5% and 6%, respectively, of the 2- hydroxypropyl derivatives of benzoylecgonine and ecgonidine. It has recently been discovered by the inventors hereof that removal of water during the reaction used to produce the 2- hydroxypropyl derivatives of benzoylecgonine and ecgomdine helps drive the reaction to the desired products and, furthermore, removal of water during or subsequent to the reaction results in a composition with enhanced stability. The novel method for the production of the compositions comprising 2-hydroxypropyl derivatives of benzoylecgonine and ecgonidine and the enhanced stability of the resulting composition may provide advantages over the prior art methods and compositions that can be appreciated by one of skill in the art.
SUMMARY
The invention described herein fulfills the needs described above. In one embodiment, this invention provides a method for preparing a benzoylecgonine composition comprising the steps of:
(a) contacting benzoylmethylecgonine and propylene glycol in the presence or absence of water to form a reaction mixture;
(b) maintaining the reaction mixture at a temperature between about 50° and 100°C; and
(c) subsequently or simultaneously removing water from the reaction mixture.
In another embodiment, this invention provides novel benzoylecgonine compositions comprising at least about 2% 2-hydroxypropyl benzoylecgonine esters, at least about 2% 2-hydroxypropyl ecgonidine esters, less than about 0.1% benzoylmethylecgonine and between about 0% and about 4% water.
The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.
DETAILED DESCRIPTION As used herein:
Percentage content of particular components of a composition refers to the percentage of the weight of that component represented in the weight of the final composition. For example, a composition comprising 5% water is 5% water w/w of the composition.
The term "benzoylmethylecgonine" or "BME" refers to the chemical entity 3- benzoyloxy-2-carbomethyoxy-8-methyl-8-azabicyclo[3.2.1]octane. BME can exist in four diastereomeric forms (cocaine, pseudococaine, allococaine and allopseudococaine) and each diastereomer has two optical antipodes. Any one of these compounds or any combination of more than one of these compounds is encompassed by the invention herein. BME is typically prepared as a salt (e.g., cocaine HC1) or a reduced base (e.g., cocaine alkaloid) according to known methods.
The terms "2-hydroxypropyl ester", "2-hydroxypropyl ester derivatives", "2-HP derivatives" and other similar terms used herein, refer to the 2-hydroxypropyl ester derivatives of benzoylecgonine, ecgonine and/or ecgonidine. When these terms are used in general herein, they are meant to refer to any one or more of these 2-hydroxypropyl ester derivatives. The term "substantially all", when referring to the reaction of benzoylmethylecgonine, means that more than approximately 95% of the benzoylmethylecgonine has reacted, preferably more than approximately 99%, more preferably, more than approximately 99.5% and most preferably, more than approximately 99.9%.
This invention provides a method for preparing a benzoylecgonine composition comprising the steps of:
(a) contacting benzoylmethylecgonine and propylene glycol in the presence or absence of water to form a reaction mixture;
(b) maintaining the reaction mixture at a temperature between about 50° and 100°C; and
(c) subsequently or simultaneously removing water from the reaction mixture.
The methods of this invention advantageously produce a benzoylecgonine composition that is proportionately higher in 2-hydroxypropyl ester derivatives and/or demonstrates enhanced stability as compared to benzoylecgonine compositions comprising or produced in excess water. Using the methods of this invention, it is possible to enhance the relative content of one or more specific 2-HP ester derivatives. In particular, the methods of this invention may be used to produce a benzoylecgomne composition that has an enhanced relative content of the 2- hydroxypropyl esters of benzoylecgonine (2-HP BEc). It is believed that 2-HP BEc may have superior activity for particular indications (including, without limitation, one or more of the indications described in US patents 4,469,700; 4,512,996; 4,556,663; 5,376,667; 5,559,123 and 5,663,345) as compared with other 2-HP esters.
The methods of this invention may be carried out in any suitable reaction vessel, including glass and stainless steel flasks. The starting material, benzoylmethylecgonine, may be used as the free base prepared by alkaline reduction of cocaine HC1 (converted using known techniques such as,
for example, US patent 5,316,661, column 11, lines 45-52) or directly from the trophane alkaloid (which is a preferred starting material). These materials can be obtained commercially or may be prepared using known synthetic processes. Although the reaction may be quenched at any time, the reaction is preferably maintained until substantially all of the benzoylmethylecgonine has reacted. In one preferred embodiment, the reaction is monitored by observing the amount of 2- HP BEc produced in addition to observing the disappearance of benzoylmethylecgonine. Ideally, the reaction should be quenched when the maximum amount of 2-HP BEc has been produced. The amount of benzoylmethylecgonine or of 2-HP BEc can be monitored during the course of the reaction using known techniques, such as gas chromatography, high performance liquid chromatography (HPLC) and/or mass spectrophotometry. These and other like techniques are well known to those of ordinary skill in the art and have been described in US patent 5,376,667 and elsewhere.
Preferably, in step (a), water is present at a ratio of water to propylene glycol of approximately 1:19. Accordingly, in one preferred embodiment, water represents approximately 5% w/w of the reaction mixture, the propylene glycol represents the remaining 95% (w/w).
In a preferred embodiment, water is added to the propylene glycol prior to addition of benzoylmethylecgonine and prior to or during heating. Preferably, the propylene glycol/water solution is stirred during heating. The reaction mixture is preferably heated to between about 45° and 80°C, more preferably, to between about 50° and 70°C and most preferably, to approximately 60°C prior to adding the benzoylmethylecgonine. At approximately 60°C, the reaction time is approximately twice as fast as that exemplified in Example 3 of US patent 5,376,667. It is anticipated that heating of the reaction mixture above about 60°C will similarly result in a decreased reaction time. However, the product made at temperatures significantly above about 60° may develop an undesirable color unless the pressure is reduced accordingly. Therefore, it is possible to run the reaction of this invention under reduced pressure and higher temperatures to produce a final product in the shortest time that has the most desirable appearance and profile.
It should be noted that the reaction may be carried out successfully in either the presence or the absence of water. In fact, the yield of 2-hydroxypropyl esters of benzoylecgonine may be
enhanced by excluding water from the reaction mixture. Regardless of whether or not water is initially added to the reaction mixture, we have found that the removal of water during or subsequent to the reaction helps to drive the reaction to the desired 2-hydroxypropyl ester derivatives and furthermore, results in a more stable final product. Water is preferably removed from the reaction mixture during the course of the reaction. Water may be removed by any known means, such as by use of water scavengers (such as molecular sieves), vacuum distillation, by fitting the reaction vessel with an open reflux condenser or conducting the reaction under a flow of an inert gas, such as nitrogen or argon (preferably, dry nitrogen or argon) (or any combination of such means). Preferably, the method of this invention is conducted in a vessel fit with an open reflux condenser, in which a stream of dry nitrogen is blown over the surface of the reaction mixture. The inventors have found that by conducting the reaction under these preferred conditions, significantly less water is present in the final product as compared to prior methods (e.g., typically approximately l%-2% versus approximately 5%). In addition, it was also found that these reaction conditions result in a final product composition that is higher in overall content of 2-hydroxypropyl ester derivatives than if the water is not removed during the reaction (at least about 2% benzoylecgonine and 2-hydroxypropyl esters of ecgonidine, respectively). Although removal of water during the course of the reaction is preferred, water can be removed after the reaction is complete, or water may be removed both during and after the reaction is complete, if desired. Molecular sieves or other conventional drying agents (such as, for example, magnesium sulfate trihydrate) may be used for this purpose.
It has been discovered surprisingly that the removal of water during the reaction and/or from the final product leads to increased stability of the resultant composition. It has also been surprisingly determined that performing the reaction in the absence of water results in an improved conversion of starting material to desired product. Without wishing to be bound by theory, we believe that these surprising results are a consequence of the particular biochemical pathways leading from the benzoylmethylecgonine to the production of the hydroxypropyl esters. Particular features of this pathway are illustrated below:
Benzoylmethylecgonine
Methylecgonine
It should be noted that transesterification rates kls k2, and k3 are impacted by the presence or absence of water, the temperature and pressure of the reaction. In addition, it should be noted that the reaction of benzoylmethylecgomne results in the production of water.
As detailed above, the methods of this invention are useful for producing improved benzoylecgonine compositions. Without limiting the generality of the foregoing, the compositions produced by the methods of this invention possess one or more of the following properties: enhanced stability (e.g., having a longer shelf life), enhanced content of 2- hydroxypropyl ester derivatives, and more cost effective manufacturing. Preferred compositions of this invention are benzoylecgonine compositions comprising at least about 2% 2- hydroxypropyl benzoylecgonine esters, at least about 2% 2-hydroxypropyl ecgonidine esters, less than about 0.1% benzoylmethylecgonine esters and less than about 4% water.
Without wishing to be bound by theory, we believe that the enhanced stability seen in the compositions of the instant invention results from the removal of water from the compositions. ' It is believed that over time, water may facilitate ester hydrolysis of the benzoylecgonine compositions. By removing water, this process is restricted. In addition, we have found surprisingly that the reaction that converts benzoylmethylecgonine to the 2-hydroxypropyl esters proceeds via transesterification, rather than hydrolysis followed by esterification. Thus, removal of water drives the reaction to form greater amounts of 2-hydroxypropyl ester derivatives and produces a final product more concentrated (enriched) in 2-hydroxypropyl ester derivatives, versus the underivatized benzoylecgonine, ecgonine and ecgonidine compounds. Lipophilic compounds, such as the 2-hydroxypropyl derivatives, are likely to possess enhanced pharmacological activity as compared to the more hydrophilic parent compounds. For example, the 2-hydroxypropyl derivatives will be more readily absorbed through the skin when administered topically, being more easily transported through the lipophilic sebum environment of the hair follicles (Int. J. Pharm. 220:63-75, 2001).
EXAMPLES
The following specific examples are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way.
Cocaine alkaloid was prepared by basification of cocaine HCl in an aqueous 10% potassium hydroxide solution until pH>10. The solution was then filtered and the slurry washed with water. The cocaine base was dried in an oven at 60°C for at least 18 hours before being used as input to the following reactions.
BEc = benzoylecgonine; Ec = ecgonine; BA = benzoic acid; Ecd = ecgonidine
Example 1 : Inert Gas Flow
2.0g of cocaine alkaloid was added to a 50ml glass stoppered jacketed flask, followed by 17g of propylene glycol and l.Og of water. The contents were stirred and placed under a steady stream of dry nitrogen with an open water condenser, the solution was maintained at 50°C until the unreacted cocaine was less than 0.1 %w/w.
Example 2: Vacuum
2.0g of cocaine alkaloid was added to a 50ml glass stoppered jacketed flask, followed by 17g of propylene glycol and l.Og of water. The contents were stirred and placed under a vacuum (25mm/Hg), and the solution was maintained at 50°C until the unreacted cocaine was less than 0.1%w/w.
Example 3: Absence of Water
2.0g of cocaine alkaloid was added to a 50ml glass stoppered jacketed flask, followed by 18g of propylene glycol. The contents were stirred and placed under a nitrogen atmosphere, the solution was maintained at 55°C until the unreacted cocaine was less than 0.1%w/w.
Example 4: 5% w/w Water
2.0g of cocaine alkaloid was added to a 50ml glass stoppered jacketed flask, followed by 17g of propylene glycol and 1.0g of water. The contents were stirred and placed under a nitrogen atmosphere, the solution was maintained at 50°C until the unreacted cocaine was less than 0.1%w/w.
Example 5: Stability testing (Absence of water)
The following table shows the changes in the relative amounts of particular components for the composition produced in Example 3 at 60°C. The last two columns represent the stability of the composition at 25°C and 40°C after 13 days. ■
BEc = benzoylecgonine; Ec = ecgonine; BA = benzoic acid; Ecd = ecgonidine; 2-HPE = 2 hydroxypropyl ester; designations A, B and C indicate different isomers of the named compound; BME = benzoylmethylecgonine.
Example 6: Stability testing (Initial 5%w/w water)
The following table shows the changes in the relative amounts of particular components for the composition produced in Example 4 at 50°C. The last two columns represent the stability of the composition at 25°C and 40°C after 13 days.
BEc = benzoylecgonine; Ec = ecgonine; B A = benzoic acid; Ecd = ecgonidine; 2-HPE = 2 hydroxypropyl ester; designations A, B and C indicate different isomers of the named compound; BME = benzoylmethylecgonine.
Conclusion: The examples shown above demonstrate that the methods according to this invention produce a benzoylecgonine composition having enhanced content of 2-hydroxypropyl derivatives and an improved stability profile. In Example 5, the total amount of hydroxypropyl benzoylecgonine esters (2-HPE Bec(A), 2-HPE Bec(B) and 2-HPE Bec(C) at the end of the reaction (and at the start of the stability trial) represents 28.8% of the composition and after 13
days at 40 °C, 81% of the hydroxypropyl benzoylecgonine esters remain. In Example 6, the total amount of hydroxypropyl benzoylecgonine esters at the end of the reaction (and at the start of the stability trial) represents 9.71% of the composition and after 13 days at 40 °C, only 61% of the hydroxypropyl benzoylecgonine esters remain.
OTHER EMBODIMENTS
A number of embodiments of the invention have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims.
Claims (10)
1. A method for preparing a benzoylecgonine composition comprising the steps of: '
(a) contacting benzoylmethylecgomne and propylene glycol in the presence or absence of water to form a reaction mixture;
(b) maintaining the reaction mixture at a temperature between about 50° and 100°C until substantially all of the benzoylmethylecgonine has reacted; and
(c) subsequently or simultaneously removing water from the reaction mixture.
2. The method according to claim 1, wherein step (a) is performed in the absence of water.
3. The method according to claim 1, wherein the water is present in step (a) in an amount equal to approximately 0-5% by weight of the reaction mixture.
4. The method according to claim 1, wherein the temperature of step (b) is approximately 60°C.
5. The method according to claim 1, wherein water is removed from the reaction mixture in step (c) by using an open reflux condenser.
6. The method according to claim 1 or 4, wherein the reaction is conducted under a stream of inert gas.
7. The method according to claim 5, wherein the inert gas is dry nitrogen.
8. The method according to claim 5, wherein the inert gas is dry argon.
9. A benzoylecgonine composition comprising benzoylecgonine, ecgonidine, 2- hydroxypropyl benzoylecgonine esters and 2-hydroxypropyl ecgonidine esters wherein the composition comprises at least about 2% 2-hydroxypropyl benzoylecgonine esters and at least about 2% 2-hydroxypropyl ecgonidine esters.
10. The benzoylecgonine composition according to claim 9, produced by the method according to claim 1.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US60/348,882 | 2001-11-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| AU2002352672A1 true AU2002352672A1 (en) | 2003-05-26 |
Family
ID=
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0599890B1 (en) | Geneserine derivatives as cholinesterase inhibitors | |
| HK1006714B (en) | Geneserine derivatives as cholinesterase inhibitors | |
| JPWO2000048982A1 (en) | Method for producing (2R)-2-propyloctanoic acid | |
| CA2438854A1 (en) | Method of preparing non-hydrated fexofenadine hydrochloride and novel crystalline form obtainable by this method | |
| US6790857B2 (en) | Benzoylecgonine compositions and methods for producing them | |
| AU2002352672A1 (en) | Novel benzoylecgonine compositions and methods for producing them | |
| JP2000503647A (en) | New manufacturing method | |
| EP0130142B1 (en) | Prostacycline derivatives, process for their preparation and their use as medicines | |
| EP0164049B1 (en) | Process for preparing hmg-coa reductase inhibtors with a 3,5-dihydroxypentanoate subunit | |
| AU777920B2 (en) | Beta-D-5-thioxylose derivatives, preparation method and therapeutic use | |
| RU2259996C2 (en) | New method for preparing $$$-(2,4-disulfophenyl)-n-tertiary-butyl nitrone and its pharmacologically acceptable salts | |
| EP4303211B1 (en) | Industrial process for the preparation of hexanoic acid, 6(nitrooxy)-,(1s,2e)-3-[(1r,2r,3s,5r)-2-[(2z)-7-(ethylamino)-7-oxo-2-hepten-1-yl]3,5-dihydroxycyclopentyl]-1-(2-phenyl ethyl)-2-propen-1-yl ester and high pure product | |
| JP2000501946A (en) | Methods for preparing intermediates for the synthesis of antifungals | |
| EP2502923B1 (en) | A method for preparing a statin compound by lactonization | |
| EP2376496B1 (en) | Synthesis of morphine-6-glucuronide or of a derivative thereof | |
| SU1072801A3 (en) | Process of preparing derivatives of prostacycline or their epimers | |
| JP2003500465A (en) | Method for producing alkoxy cinnamate | |
| JP2003528843A (en) | Preparation of carboxylic acid benzyl ester | |
| JP4397990B2 (en) | Purification method of 3-alkylflavanonol derivatives | |
| JP2001526291A (en) | Method for purifying solution of ampicillin prodrug ester | |
| JP2000515855A (en) | Method for producing dihydropyridines | |
| CA2578182A1 (en) | Improved synhesis of alkoxylated sucrose esters | |
| JP2754755B2 (en) | Optically active furyl carbinols and their production | |
| IE914318A1 (en) | Crystalline palladium tetrakis(triphenyl-phosphine) and a¹process for preparing the same | |
| KR0139717B1 (en) | Carbamic compound |