CH240068A - Process for the preparation of ampoules containing colorless aqueous solutions of a vitamin K-active compound. - Google Patents
Process for the preparation of ampoules containing colorless aqueous solutions of a vitamin K-active compound.Info
- Publication number
- CH240068A CH240068A CH240068DA CH240068A CH 240068 A CH240068 A CH 240068A CH 240068D A CH240068D A CH 240068DA CH 240068 A CH240068 A CH 240068A
- Authority
- CH
- Switzerland
- Prior art keywords
- methyl
- dioxynaphthalene
- diphosphoric acid
- vitamin
- aqueous solutions
- Prior art date
Links
- 239000007864 aqueous solution Substances 0.000 title claims description 7
- 150000001875 compounds Chemical class 0.000 title claims description 4
- 238000000034 method Methods 0.000 title claims description 4
- 229940088594 vitamin Drugs 0.000 title claims description 4
- 229930003231 vitamin Natural products 0.000 title claims description 4
- 235000013343 vitamin Nutrition 0.000 title claims description 4
- 239000011782 vitamin Substances 0.000 title claims description 4
- 150000003722 vitamin derivatives Chemical class 0.000 title claims description 4
- 238000002360 preparation method Methods 0.000 title description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- RRHGJUQNOFWUDK-UHFFFAOYSA-N Isoprene Chemical compound CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 5
- 239000002244 precipitate Substances 0.000 claims description 3
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 3
- KPZGRMZPZLOPBS-UHFFFAOYSA-N 1,3-dichloro-2,2-bis(chloromethyl)propane Chemical compound ClCC(CCl)(CCl)CCl KPZGRMZPZLOPBS-UHFFFAOYSA-N 0.000 claims description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- 239000011575 calcium Substances 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 229940043430 calcium compound Drugs 0.000 claims description 2
- 150000001674 calcium compounds Chemical class 0.000 claims description 2
- 239000001506 calcium phosphate Substances 0.000 claims description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 claims description 2
- 235000011010 calcium phosphates Nutrition 0.000 claims description 2
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims 1
- 239000003708 ampul Substances 0.000 claims 1
- 239000002699 waste material Substances 0.000 claims 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000001110 calcium chloride Substances 0.000 description 2
- 229910001628 calcium chloride Inorganic materials 0.000 description 2
- 159000000007 calcium salts Chemical class 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- XPPKVPWEQAFLFU-UHFFFAOYSA-N diphosphoric acid Chemical compound OP(O)(=O)OP(O)(O)=O XPPKVPWEQAFLFU-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229910052816 inorganic phosphate Inorganic materials 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- BRPQOXSCLDDYGP-UHFFFAOYSA-N calcium oxide Chemical compound [O-2].[Ca+2] BRPQOXSCLDDYGP-UHFFFAOYSA-N 0.000 description 1
- 239000000292 calcium oxide Substances 0.000 description 1
- ODINCKMPIJJUCX-UHFFFAOYSA-N calcium oxide Inorganic materials [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
- A61K31/355—Tocopherols, e.g. vitamin E
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
Description
Verfahren zur Herstellung von farblose wässerige tösungen einer Vitamin-K-wirksamen Terbindung enthaltenden Ampullen.
Es wurde gefunden, dass man farblose wässerige Lösungen einer Vitamin-K-wirksamen Verbindung enthaltende Ampullen dadurch erhalten kann, daB man das durch Kondensation von 2-Methyl-1, 4-dioxynaphthalin mit Phosphoroxychlorid entstandene rohe, etwas Phosphoroxychlorid enthaltende 2-Methyl-1, -dioxynaphthalin-diphosphorsäure- tetrachlorid mit Wasser bei Gegenwart von Basen zersetzt, mit einer Calciumverbindung die 2-Methyl-1, 4-dioxynaphthalin-diphosphor- saure in das Dicalciumsalz überführt und die von dem im rohen 2-Methyl-1, 4-dioxynaph thalin-diphosphorsäuredichlorid enthaltenen Phosphoroxychlorid herstammende Phosphorsaure als Calciumphosphat ausfällt, die calciumphosphatfreie Lösung zum Sieden erhitzt, das ausgefallene 2-Methyl-1,
4-dioxy- naphthalin-diphosphorsäure-dicalcium inWas- ser lost und die Lösung in Ampullen abfüllt.
Die gemäss dem neuen Verfahren hergestellten wässerigen Losungen des Dicalciumsalzes der 2-Methyl-1, 4-dioxynaphthalin-diphosphorsäure sind, wie sich zeigte, so rein, dass sie ohne weiteres in Ampullen abgefüllt und so für therapeutische Zwecke brauchbar sind.
Beispiel 1 :
Man gibt eine Lösung von 10 Teilen 2-Methyl-1, 4-dioxynaphthalin in100 Teilen Pyridin unter guter Kühlung zu 150 Teilen Phosphoroxychlorid. Nach Beendigung der Umsetzung trennt man das gebildete Diphosphorsäuredichlorid von dem ausgefallenen Pvridinhydrochlorid durch Extraktion mit Benzol ab und dampft die Benzollosung im Vakuum ein. Der Rückstand wird ohne weitere Reinigung vorsichtig mit Wasser unter Zusatz von Natronlauge zersetzt und die neu- trale Losung mit einer Lösung von 20 Teilen Calciumchlorid gemischt, so dal3 das Volumen ca. 300-500 Raumteile beträgt.
Das ausfallende Calciumphosphat wird abfiltriert und das klare Filtrat zum Sieden erhitzt, worauf sich das Calciumsalz der 2-Me thyl-14-dioxynaphthalin-diphosphorsäure als schweres sandiges Pulver abscheidet. Es wird hei¯ abfiltriert und mit heissem Wasser ausgewaschen, gelöst und die Losung in Ampul- len abgefüllt.
Das Salz hat die Formel
C11H8O8P2Ca2. 4 H2O, aus dem jedoch ein Teil des Kristallwassers sehr leicht, schon bei Zimmertemperatur, ent- weicht. Es ist in kaltem Wasser leichter lös- lich als in heissem.
Beispiel 2 :
Man rührt eine Mischung von 170 Teilen Phosphoroxychlorid und 40 Teilen Toluol und gibt unter Kiihlung eine Suspension von 17, 4 Teilen 2-Methyl-1,4-dioxynaphthalin in 50 Teilen Dimethylanilin und 150 Teilen To luol hinzu. Nach Beendigung der Umsetzung destilliert man das überschüssige Phosphor- oxychlorid und das Toluol im Vakuum ah und zersetzt den Rückstand durch Wasserzusatz bei einer Temperatur von ca. 20-30 .
Die wässerige L¯sung wird durch Sodazusatz neutralisiert und anorganisches Phosphat durch Zugabe von 40 Teilen Calciumchlorid ausgefÏllt Man. filtriert den Phosphatnieder- sehlag ab und erhitzt das Filtrat. das ein Volumen von ca. 500-1000 Raumteilen hat, zum Sieden. Man erhÏlt eine Ausbeute an Calciumsalz von mindestens 80% der Theorie.
Das ausgeschiedene 2-Methyl-1, 4-dioxynaph thalin-diphosphorsäure-diealeium lsird iII Wasser gelöst und die Losung in Ampullen ahgefüllt.
Beispiel 3 : -ALlait kondensiert 17, 4 Teile 9-Methyl-14- dioxynaphthalin ebenso wie in Beispiel 2 und zersetzt das rohe Diphosphorsäure-dichlorid nach dem Abdampfen des überschüssigen Phosphoroxychlorids und des Toluols mit Wasser unter Hinzufügen von Calciumoxyd.
Dann trennt man anorganische Phosphate und a Dimethylanilin ab und erhitzt die wässerige Lösung zum Sieden. Aus dem abgeschiedenen Dicaiciumsalz der 2-Methyl 1. 4-dioxynaphthalin-diphosphorsäure wird eine Losung hergestellt und die L¯sung in Ampullen abgefüllt.
Process for the preparation of colorless aqueous solutions of a vitamin K-active compound containing ampoules.
It has been found that ampoules containing colorless aqueous solutions of a vitamin K-active compound can be obtained by adding the crude 2-methyl-1, which contains a little phosphorus oxychloride and which is formed by the condensation of 2-methyl-1,4-dioxynaphthalene with phosphorus oxychloride , -dioxynaphthalene-diphosphoric acid tetrachloride decomposed with water in the presence of bases, with a calcium compound the 2-methyl-1, 4-dioxynaphthalene-diphosphoric acid is converted into the dicalcium salt and that of the crude 2-methyl-1, 4- dioxynaphthalin-diphosphoric acid dichloride containing phosphorus oxychloride precipitates as calcium phosphate, the calcium phosphate-free solution is heated to boiling, the precipitated 2-methyl-1,
Dissolve 4-dioxynaphthalene-diphosphoric acid-dicalcium in water and fill the solution into ampoules.
The aqueous solutions of the dicalcium salt of 2-methyl-1,4-dioxynaphthalene-diphosphoric acid prepared according to the new process are so pure that they can easily be filled into ampoules and thus usable for therapeutic purposes.
Example 1 :
A solution of 10 parts of 2-methyl-1,4-dioxynaphthalene in 100 parts of pyridine is added to 150 parts of phosphorus oxychloride with good cooling. After the reaction has ended, the diphosphoric acid dichloride formed is separated off from the precipitated pvridine hydrochloride by extraction with benzene and the benzene solution is evaporated in vacuo. Without further purification, the residue is carefully decomposed with water with the addition of sodium hydroxide solution and the neutral solution is mixed with a solution of 20 parts of calcium chloride so that the volume is approx. 300-500 parts by volume.
The precipitated calcium phosphate is filtered off and the clear filtrate is heated to boiling, whereupon the calcium salt of 2-methyl-14-dioxynaphthalene-diphosphoric acid is deposited as a heavy, sandy powder. It is filtered off hot, washed out with hot water, dissolved and the solution filled into ampoules.
The salt has the formula
C11H8O8P2Ca2. 4 H2O, from which, however, part of the crystal water escapes very easily, even at room temperature. It is more soluble in cold water than in hot water.
Example 2:
A mixture of 170 parts of phosphorus oxychloride and 40 parts of toluene is stirred and a suspension of 17.4 parts of 2-methyl-1,4-dioxynaphthalene in 50 parts of dimethylaniline and 150 parts of toluene is added with cooling. After the reaction has ended, the excess phosphorus oxychloride and the toluene are distilled in vacuo and the residue is decomposed by adding water at a temperature of about 20-30.
The aqueous solution is neutralized by adding soda and inorganic phosphate is precipitated by adding 40 parts of calcium chloride. the phosphate precipitate is filtered off and the filtrate is heated. which has a volume of approx. 500-1000 parts of space, for boiling. A calcium salt yield of at least 80% of theory is obtained.
The excreted 2-methyl-1,4-dioxynaphthalene-diphosphoric acid-diealeium is dissolved in water and the solution is filled into ampoules.
Example 3: ALlait condenses 17.4 parts of 9-methyl-14-dioxynaphthalene as in Example 2 and decomposes the crude diphosphoric acid dichloride after the excess phosphorus oxychloride and toluene have been evaporated off with water with the addition of calcium oxide.
Inorganic phosphates and a dimethylaniline are then separated off and the aqueous solution is heated to the boil. A solution is prepared from the precipitated dicaicium salt of 2-methyl 1,4-dioxynaphthalene-diphosphoric acid and the solution is filled into ampoules.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH240068T | 1942-03-03 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH240068A true CH240068A (en) | 1945-11-30 |
Family
ID=4461602
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH240068D CH240068A (en) | 1942-03-03 | 1942-03-03 | Process for the preparation of ampoules containing colorless aqueous solutions of a vitamin K-active compound. |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH240068A (en) |
-
1942
- 1942-03-03 CH CH240068D patent/CH240068A/en unknown
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