CN1038033C - Process for producing methanediphosphonate compound - Google Patents

Process for producing methanediphosphonate compound Download PDF

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CN1038033C
CN1038033C CN94190078A CN94190078A CN1038033C CN 1038033 C CN1038033 C CN 1038033C CN 94190078 A CN94190078 A CN 94190078A CN 94190078 A CN94190078 A CN 94190078A CN 1038033 C CN1038033 C CN 1038033C
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compound
phosphonic acid
methyl
ethylhexyl phosphonic
reaction
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CN1102750A (en
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高西庆次郎
内吕拓实
川道纪雄
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Toray Industries Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3839—Polyphosphonic acids
    • C07F9/3865—Polyphosphonic acids containing sulfur substituents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4025—Esters of poly(thio)phosphonic acids
    • C07F9/4043—Esters of poly(thio)phosphonic acids containing sulfur substituents

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

制备1-烷硫基甲基二膦酸化合物或1-芳硫基甲基二膦酸化合物的方法，其特征在于在金属氧化物的存在下按下面所示的反应方案进行缩合反应，其中R1可相同或不同为有1到6个碳原子的直链或支链烷基；R1是药理上允许的阳离子、氢或有1到6个碳原子的直链或支链烷基，R2是烷基或芳基。该方法与传统方法相比产率大大提高，同时简化了纯化工艺，因而有很高的经济和工业价值。

The method for preparing 1-alkylthiomethyl diphosphonic acid compound or 1-arylthiomethyl diphosphonic acid compound is characterized in that the condensation reaction is carried out in the presence of a metal oxide according to the reaction scheme shown below, wherein R 1 can be the same or different as a straight chain or branched chain alkyl group with 1 to 6 carbon atoms; R1 is a pharmacologically acceptable cation, hydrogen or a straight chain or branched chain alkyl group with 1 to 6 carbon atoms, R 2 is alkyl or aryl. Compared with the traditional method, the yield of the method is greatly improved, and the purification process is simplified at the same time, so the method has high economic and industrial value.

Description

The preparation method of methanediphosphonatecompound compound
The present invention relates to the preparation method of methanediphosphonatecompound compound, these compounds can be used as metal chelator or medicine such as anti-inflammatory medicaments, resisting rheumatoid disease medicine, bone metabolism disease therapeuticing medicine etc.
Synthetic 1-alkylthio-or the method for 1-arylthio-methyl di 2 ethylhexyl phosphonic acid for example be described on Japanese patent laid-open publication gazette 4-29676 number (Japanese Examined PatentPublication (Kokoku) No.4-29676).In the described condensation reaction of this patent, methyl di 2 ethylhexyl phosphonic acid four alkane esters change into the corresponding metal derivative by introducing metal agent such as sodium hydride, then with various disulphide and this derivatives reaction to synthesize 1-alkylthio-or 1-arylthio-methyl di 2 ethylhexyl phosphonic acid four alkane esters.This condensation reaction generates desired compound with low-yield.Yet a large amount of disulphide and methyl di 2 ethylhexyl phosphonic acid four alkane esters and reaction are paid product mercaptan and are recovered in the thick product, must use the operation such as the silica gel column chromatography partition method of industrial costliness for purifying.Because desired compound methanediphosphonatecompound compound is extremely useful in fields such as pharmaceutical compositions, aforesaid method provides a large amount of compounds unsatisfactorily, thereby need seek simple and economic method.
The greatest problem of the condensation reaction of describing in Japanese Examined Patent Publication (Kokoku) No.4-29676 is a still unreacted of a large amount of raw material methyl di 2 ethylhexyl phosphonic acid four alkanoic acids and disulphide, separates from raw material and the purifying desired product is required great effort very much.If can reduce the amount of unreacted methyl di 2 ethylhexyl phosphonic acid four alkane esters and disulphide, just can provide excellent 1-alkylthio-or the method for 1-arylthio-methyl di 2 ethylhexyl phosphonic acid for preparing.
Because to studying in great detail of condensation reaction, the inventor finds to add metal oxide such as magnesium oxide can obtain the product 1-alkylthio methyl di 2 ethylhexyl phosphonic acid four alkane esters of being wanted or 1-arylthio methyl di 2 ethylhexyl phosphonic acid four alkane esters with high yield in condensation reaction.In addition, find that the metal-salt of paying product mercaptan and the magnesium oxide in the reaction forms mixture, this mixture can be borrowed at an easy rate to filter and separate from want product.Therefore, the purpose of this invention is to provide a kind of 1-alkylthio methanediphosphonatecompound compound of medicine or preparation method of 1-arylthio methanediphosphonatecompound compound of being used as.
The invention provides the preparation method of a kind of formula (I) methanediphosphonatecompound compound: R wherein 1Can be identical or different, be the positively charged ion that allows on the pharmacology, hydrogen atom or the straight or branched alkyl of 1 to 6 carbon atom is arranged; And R 2Be alkyl or aryl, the method is characterized in that in the presence of metal oxide, the metal derivative of the methyl di 2 ethylhexyl phosphonic acid four alkane esters of formula (II) Wherein R ' can be identical or different for the straight or branched alkyl of 1 to 6 carbon atom is arranged, with dialkyl group two sulphur or diaryl two reaction of Salmon-Saxl of formula (III)
R 2S-SR 2R wherein 2Represent alkyl or aryl.
The present invention prepares 1-alkylthio methanediphosphonatecompound compound or 1-arylthio methanediphosphonatecompound compound is illustrated in the following reaction formula (A):
Figure C9419007800062
R wherein 1' representative has the straight or branched alkyl of 1 to 6 carbon atom, and R 2Represent alkyl or aryl.
Temperature of reaction and reaction times are depended on solvent for use, reaction reagent and raw material, and following described condition only is preferred condition.
Heating methyl di 2 ethylhexyl phosphonic acid four alkane esters in the presence of alkali and metal oxide, add disulphide then to react, filter reaction mixture is almost completely to remove the mercaptan as metal-salt, with the mixture of acid treatment filtrate with acquisition 1-alkylthio or 1-arylthio methyl di 2 ethylhexyl phosphonic acid four alkanoic acids and a small amount of disulphide.In this case, if do not use metal oxide to make reaction additives, desired product 1-alkylthio-or the productive rate of 1-arylthio methyl di 2 ethylhexyl phosphonic acid four alkane esters is very low, and simultaneously big content of starting materials methyl di 2 ethylhexyl phosphonic acid four alkane esters and disulphide are recovered.In addition, in this case, solvent for use preferably has high boiling point and low polar solvent such as toluene; Alkali does not preferably cause the alkali of transesterification reaction such as potassium tert.-butoxide etc.Though magnesium oxide, zinc oxide, cupric oxide etc. can both preferably use magnesium oxide as metal oxide as reaction additives.If potassium tert.-butoxide as alkali, can further improve productive rate by removing the product trimethyl carbinol of paying that forms between the reaction period.With respect to the amount of methyl di 2 ethylhexyl phosphonic acid four alkane esters, the molar weight of alkali, metal oxide and disulphide is 1 to 5 molar equivalent.Temperature of reaction is between room temperature and solvent for use boiling point, and the temperature that is higher than the temperature of pure boiling point under the uncle or is higher than the azeotropic temperature of the trimethyl carbinol is preferred.Reaction times is 1 to 5 hour.
Though being used for the alkyl and the aryl in diaryl two sulphur of dialkyl group two sulphur of the present invention can be selected without restriction, preferred alkyl is straight or branched alkyl or (mixing) cycloalkyl, for example methyl that 1 to 20 carbon atom is arranged, ethyl, propyl group, sec.-propyl, butyl, sec-butyl, the tertiary butyl, amyl group, cyclobutyl, cyclopentyl, cyclohexyl, ring octyl group etc.Alkyl comprises the group of the two keys of band, and comprises the substituent alkyl that has such as halogen, alkoxyl group, CN, nitro, amino, ester group, phenyl ring.Aryl comprises phenyl, naphthyl, quinolyl, isoquinolyl, thienyl, pyridyl, pyrryl, benzothiazolyl, benzoxazolyl etc.Aryl comprises the aryl that does not replace and replace.Substituting group comprises halogen, alkyl, alkoxyl group, siloxy-, alkylthio, nitro, amino etc.
The hydrolysis of 1-alkylthio methyl di 2 ethylhexyl phosphonic acid four alkane esters or 1-arylthio methyl di 2 ethylhexyl phosphonic acid four alkane esters provides corresponding di 2 ethylhexyl phosphonic acid.Hydrolysis can be undertaken by known general method.For example hydrolysis can be carried out with salt acid treatment ester between room temperature to 100 ℃.Even ester is and the mixture of the disulphide that is used for synthetic ester that after the hydrolysis, disulphide is easy to extraction or filters and remove.The di 2 ethylhexyl phosphonic acid compound of Huo Deing can change into its salt by currently known methods like this.
Positively charged ion representation metal ion of Yun Xuing or ammonium ion NR in the present invention 4Wherein R is a hydrogen atom, or the straight or branched alkyl of 1 to 7 carbon atom, particularly preferred metal ion are arranged is the positively charged ion of basic metal such as lithium, sodium, potassium and alkaline-earth metal such as magnesium, calcium positively charged ion.But positively charged ions such as other metal such as aluminium, zinc, iron are also included among the present invention.Ammonium ion comprises the ammonium ion and the quaternary ammonium ion of ammonia, primary amine, secondary amine and tertiary amine.Ammonium ion comprises the ammonium ion and the tetramethylammonium ion of ammonia, methylamine, dimethylamine, Trimethylamine 99, ethamine, diethylamine, triethylamine, propylamine, dipropyl amine, Isopropylamine, Diisopropylamine, butylamine, dibutylamine, isobutylamine, TERTIARY BUTYL AMINE, Monoethanolamine MEA BASF, diethanolamine, trolamine, Tetrylammonium ion etc. like this.Wherein sodium and potassium cationic, the ammonium ion of nitrogen or alkylamine is preferred.
With add above-mentioned metal oxide be feature prepare the 1-alkylthio-or the method for 1-arylthio-methanediphosphonatecompound compound compare with the method for routine and improved productive rate greatly, simplified purifying process simultaneously, from economy and industrial point of view, this is of great use.
Embodiment
The following example is intended to explain rather than restriction the present invention.Embodiment 1 4-methylthio phenyl sulfenyl methyl di 2 ethylhexyl phosphonic acid (R in the general formula (I) 1=H; R 2=4-MeSPh)
(making the method for metal oxide with magnesium oxide)
Under the argon atmosphere, will heat by the suspension returning that 0.99g potassium tert.-butoxide, 0.48g magnesium oxide and 10ml toluene are formed, 1.32ml methyl di 2 ethylhexyl phosphonic acid four isopropyl esters are added in this suspension.At this moment, remove trimethyl carbinol azeotropic mixture, keep reaction mixture at initial concentration to replenish the solvent of removing thereby add fresh toluene to this reaction mixture with distillation plant.After this operation is carried out 30 minutes, add the solution of forming by 2.48g 4,4 '-diformazan sulfenyl phenylbenzene two sulphur and 10ml toluene, heating is 4 hours under refluxing, and removes the trimethyl carbinol with distillation simultaneously.With the reaction mixture cool to room temperature, remove by filter insoluble solid.Under vigorous stirring, add 50ml 1.5N hydrochloric acid.Separate organic layer, with 10ml toluene extraction waterbearing stratum.Re-extract 3 times.Merge organic layer and use dried over mgso, steam solvent and obtain four isopropyl esters of desired compound di 2 ethylhexyl phosphonic acid and the mixture of disulphide.With thick product reflux 5 hours in the 20ml concentrated hydrochloric acid, reaction mixture is diluted to 2 times of original volume with 1.5N hydrochloric acid.Removing the disulphide that still exists, the aqueous solution is concentrated into dried white solid with 8ml toluene wash water solution 3 times.White solid gets 1.23g with acetone/methylene dichloride recrystallization and wants compound (productive rate 93% fusing point 215 to 216 ℃ (decomposition)).After the drying, white solid and yellow soda ash are reacted in water,, after activated carbon treatment disodium salt solution, filtration and concentrating this solution, get the disodium salt (productive rate 93% of corresponding di 2 ethylhexyl phosphonic acid with this salt of ethanol/water recrystallization to change into disodium salt; Fusing point is higher than 300 ℃).
Disodium salt 1HNMR (D 2O, ppm)
2.49(s，3H)，3.23(t，J＝20H2，1H)，
7.25-7.32(m，2H)，7.51-7.58(m，2H)。
The IR of disodium salt (KBr, cm -1)
1479，1197，1158，1110，1071，928
The MASS of disodium salt (FAB) m/2 375 (M+H)-1
To C 8H 10O 6S 2P 2Na 2Ultimate analysis
Calculated value: C25.68% H2.70%
Analytical value: C25.71% H2.73% embodiment 2 4-methylthio phenyl sulfenyl methyl di 2 ethylhexyl phosphonic acids (R in the general formula (I) 1=H; R 2=4-MeSPh) (make the method for metal oxide with zinc oxide)
Repeat the method for embodiment 1, difference is to replace magnesium oxide with 0.98g zinc oxide, and the productive rate of the compound of is 90%.Embodiment 3 4-methylthio phenyl sulfenyl methyl di 2 ethylhexyl phosphonic acid (R in general formula (I) 1=H; R 2=4-MeSPh) (make metal oxide) with cupric oxide
Repeat the method for embodiment 1, part is not to replace oxide compound with the 0.95g cupric oxide, and the productive rate of the compound of is 85%.Embodiment 4 4-chlorobenzene sulfenyl methyl di 2 ethylhexyl phosphonic acid (R in general formula (I) 1=H; R 2=4-Cl-Ph)
Repeating the method for embodiment 1, difference is 4,4 '-dichloro phenylbenzene two sulphur are as raw material disulphide, the productive rate 92% of the compound of.
To C 7H 7O 6ClSP 2Na 2Ultimate analysis
Calculated value: C23.19% H1.95%
Analytical value: C23.22% H1.93% Comparative Examples 4-methylthio phenyl sulfenyl methyl di 2 ethylhexyl phosphonic acid (R in general formula (I) 1=H; R 2=4-MeSPh) (make the method for reaction additives without magnesium oxide)
Repeat the method for embodiment 1, difference is without magnesium oxide, by raw material methyl di 2 ethylhexyl phosphonic acid four isopropyl esters obtain the compound of wanting and by condensed products (IV) not:
For the thick product methyl di 2 ethylhexyl phosphonic acid of obtain, disodium salt is not carried out recrystallization as embodiment 1 is described, measure the compound of wanting and the ratio of condensed products not.This ratio is by crude product mixture 1HNMR spectrogram (compound of wanting: 3.23ppm, t, J=20Hz, H; Condensed products: 2.12ppm not, t, J=20Hz, 2H) in phosphonate group a proton integrated value calculate.The result want compound and not condensed products through being 2: 5 (mol ratio), show that when not having metal oxide the productive rate of the compound of wanting is about 30%.
Industrial applicability
To add above-mentioned metal oxide as the preparation 1-alkylthio group of feature-or 1-virtue sulphur The method of base-methanediphosphonatecompound compound is compared with the method for routine and has greatly been improved productive rate, Simplified simultaneously purifying process, from economy and industrial point of view, this is of great use.

Claims (2)

1. the method for preparation formula (I) methanediphosphonatecompound compound, R wherein 1Can be identical or different, be the positively charged ion that allows on the pharmacology, hydrogen atom or the straight or branched alkyl of 1 to 6 carbon atom is arranged; And R 2Be alkyl or aryl, the method is characterized in that in the presence of metal oxide, the metal derivative of the methyl di 2 ethylhexyl phosphonic acid four alkane esters of formula (II) Wherein R ' can be identical or different for the straight or branched alkyl of 1 to 6 carbon atom is arranged, with dialkyl group two sulphur or diaryl two reaction of Salmon-Saxl of formula (III)
R 2S-SR 2R wherein 2Represent alkyl or aryl.
2. formula (I) methanediphosphonatecompound compound
Figure C9419007800031
R wherein 1Can be identical or different, be the positively charged ion that allows on the pharmacology, hydrogen atom or the straight or branched alkyl of 1 to 6 carbon atom is arranged; And R 2It is the aryl that alkylthio replaces.
CN94190078A 1993-02-25 1994-02-23 Process for producing methanediphosphonate compound Expired - Fee Related CN1038033C (en)

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JP36832/93 1993-02-25

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CN (1) CN1038033C (en)
AU (1) AU674059B2 (en)
FI (1) FI944998L (en)
TW (1) TW346489B (en)
WO (1) WO1994019359A1 (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU699641B2 (en) * 1994-08-24 1998-12-10 Toray Industries, Inc. Process for production of methanediphosphonic acid compound
WO2010026701A1 (en) * 2008-09-03 2010-03-11 国立大学法人東北大学 Osteogenesis promoter comprising [4-(methylthio)phenylthio]methanebisphosphonic acid or pharmaceutically acceptable salt thereof as active ingredient

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5942395A (en) * 1982-07-29 1984-03-08 サノフイ Antiinflammatory product derived from methylene-diphosphonic acid
JPH0377894A (en) * 1989-08-18 1991-04-03 Toray Ind Inc Methylene diphosphonic acid compound

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH675422A5 (en) * 1988-03-31 1990-09-28 Symphar Sa

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5942395A (en) * 1982-07-29 1984-03-08 サノフイ Antiinflammatory product derived from methylene-diphosphonic acid
JPH0377894A (en) * 1989-08-18 1991-04-03 Toray Ind Inc Methylene diphosphonic acid compound

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FI944998A7 (en) 1994-10-24
AU674059B2 (en) 1996-12-05
TW346489B (en) 1998-12-01
FI944998A0 (en) 1994-10-24
CN1102750A (en) 1995-05-17
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KR950701338A (en) 1995-03-23

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