CN1363556A - Process for preparing (cycloheptylamino) methylene biphosphonic acid - Google Patents
Process for preparing (cycloheptylamino) methylene biphosphonic acid Download PDFInfo
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- CN1363556A CN1363556A CN 02112561 CN02112561A CN1363556A CN 1363556 A CN1363556 A CN 1363556A CN 02112561 CN02112561 CN 02112561 CN 02112561 A CN02112561 A CN 02112561A CN 1363556 A CN1363556 A CN 1363556A
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- CN
- China
- Prior art keywords
- suberyl
- methylenediphosphonate
- mdp
- amido
- preparation
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- 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.)
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- -1 (cycloheptylamino) methylene Chemical group 0.000 title abstract description 7
- 239000002253 acid Substances 0.000 title abstract 2
- 238000004519 manufacturing process Methods 0.000 title abstract 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 20
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 claims abstract description 10
- VXVVUHQULXCUPF-UHFFFAOYSA-N cycloheptanamine Chemical compound NC1CCCCCC1 VXVVUHQULXCUPF-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229940102859 methylene diphosphonate Drugs 0.000 claims description 34
- MBKDYNNUVRNNRF-UHFFFAOYSA-N medronic acid Chemical compound OP(O)(=O)CP(O)(O)=O MBKDYNNUVRNNRF-UHFFFAOYSA-N 0.000 claims description 17
- 238000010438 heat treatment Methods 0.000 claims description 12
- 238000010992 reflux Methods 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 238000004821 distillation Methods 0.000 claims description 8
- 238000005903 acid hydrolysis reaction Methods 0.000 claims description 6
- 239000013078 crystal Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims description 6
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 claims description 6
- SJHCUXCOGGKFAI-UHFFFAOYSA-N tripropan-2-yl phosphite Chemical compound CC(C)OP(OC(C)C)OC(C)C SJHCUXCOGGKFAI-UHFFFAOYSA-N 0.000 claims description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 239000011259 mixed solution Substances 0.000 claims description 3
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 claims description 3
- 206010013786 Dry skin Diseases 0.000 claims description 2
- 239000012141 concentrate Substances 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 230000001376 precipitating effect Effects 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000010521 absorption reaction Methods 0.000 abstract description 2
- 210000000988 bone and bone Anatomy 0.000 abstract description 2
- 230000003301 hydrolyzing effect Effects 0.000 abstract 1
- 239000003112 inhibitor Substances 0.000 abstract 1
- 229940122361 Bisphosphonate Drugs 0.000 description 4
- 150000004663 bisphosphonates Chemical class 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000009776 industrial production Methods 0.000 description 3
- JJJOZVFVARQUJV-UHFFFAOYSA-N 2-ethylhexylphosphonic acid Chemical compound CCCCC(CC)CP(O)(O)=O JJJOZVFVARQUJV-UHFFFAOYSA-N 0.000 description 2
- OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 description 2
- 208000006386 Bone Resorption Diseases 0.000 description 2
- 229940078581 Bone resorption inhibitor Drugs 0.000 description 2
- 208000001132 Osteoporosis Diseases 0.000 description 2
- 230000024279 bone resorption Effects 0.000 description 2
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- LWRDQHOZTAOILO-UHFFFAOYSA-N incadronic acid Chemical compound OP(O)(=O)C(P(O)(O)=O)NC1CCCCCC1 LWRDQHOZTAOILO-UHFFFAOYSA-N 0.000 description 2
- 229950006971 incadronic acid Drugs 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- WRUUGTRCQOWXEG-UHFFFAOYSA-N pamidronate Chemical compound NCCC(O)(P(O)(O)=O)P(O)(O)=O WRUUGTRCQOWXEG-UHFFFAOYSA-N 0.000 description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- 208000037147 Hypercalcaemia Diseases 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 229940062527 alendronate Drugs 0.000 description 1
- 229960004343 alendronic acid Drugs 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- CGZZMOTZOONQIA-UHFFFAOYSA-N cycloheptanone Chemical compound O=C1CCCCCC1 CGZZMOTZOONQIA-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 1
- 230000000148 hypercalcaemia Effects 0.000 description 1
- 208000030915 hypercalcemia disease Diseases 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000002903 organophosphorus compounds Chemical class 0.000 description 1
- 229940046231 pamidronate Drugs 0.000 description 1
- 229960003978 pamidronic acid Drugs 0.000 description 1
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 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 description 1
Abstract
A process for preparing (cycloheptylamino methylene biphosphonic acid as bone absorption inhibitor is prepared through reacting trialkyl phosphite on cycloheptylamine and trialkyl orthoformate, adding hydrochloric acid and hydrolyzing. Its advantages include gentle reaction condition and simple operation.
Description
Technical field
The invention belongs to Western medicine compounds preparation method, be specifically related to the preparation method of a kind of bisphosphonates bone resorption inhibitor (suberyl amido) methylenediphosphonate (MDP).
Background technology
Osteoporosis (Osteoposis) is a kind of multiple disease of serious threat human health, and China has classified it as one of three kinds of geriatric diseases of emphasis tackling key problem.The bisphosphonates medicine has very strong affinity as bone resorption inhibitor to calcium phosphate, and the requirement that its specific absorption that suppresses hydroxyapatite crystal suppresses formation and growth is much lower, so low dose can suppress bone resorption and produce curative effect.The bisphosphonates medicine is at home and abroad developed in recent years rapidly, not only is used for prevention and treatment of osteoporosis clinically, also is used for the treatment of concurrent hypercalcemia of malignant tumour and malignant metastatic tumor of bone.(suberyl amido) methylenediphosphonate (MDP) (Incadronate, YM175) belong to third generation di 2 ethylhexyl phosphonic acid, its bone resorption restraining effect is respectively s-generation di 2 ethylhexyl phosphonic acid Alendronic acid disodium (Alendronate), Pamidronate Disodium (Pamidronate) 10 times and 50 times, is the bisphosphonates medicine that has future.
The synthetic route of (suberyl amido) methylenediphosphonate (MDP) reported in literature as:
1.CN1022630C report, by its preparation example 1 described route be cycloheptylamine and triethyl orthoformate and diethyl phosphite Hybrid Heating react (suberyl amido) methylenediphosphonate (MDP) tetraethyl-fat.After the reaction, at first should cool off, under reduced pressure, reactant be concentrated, to get rid of unreacted diethyl phosphite and triethyl orthoformate, then residuum is carried out purifying with silica gel column chromatography, just obtain pure product (suberyl amido) methylenediphosphonate (MDP) tetraethyl ester.Again with hydrochloric acid hydrolysis get final product (suberyl amido) methylenediphosphonate (MDP), see reaction formula ().
Reaction formula (one):
The purifying of (suberyl amido) methylenediphosphonate (MDP) tetraethyl ester needs chromatography column to separate, and is unsuitable for big industrial production.
2.CN1061661C report, adopt the reaction of cycloheptylamine and ethyl formate, or adopt suberone and methane amide and ammonium formate reaction, make N-suberyl methane amide, add hydrochloric acid hydrolysis and make (suberyl amido) methylenediphosphonate (MDP) again with after the phosphorus trichloride reacting by heating, see reaction formula (two).
Reaction formula (two):
Though this method has advantage, must pass through intermediate reaction earlier, obtain intermediate product N-suberyl methane amide, it must bring certain influence to reaction control and purifying products.As when preparing intermediate product N-suberyl methane amide, need reflux 5-7 hour, and boil off low-boiling-point substance and need underpressure distillation, dripping phosphorus trichloride needs carry out or the like under the ice bath cooling.
Summary of the invention
The objective of the invention is to design a kind of more rational new preparation method of big industrial production, operational path that is suitable for.The invention provides the preparation method of a kind of (suberyl amido) methylenediphosphonate (MDP).
The present invention adopts cycloheptylamine and alkyl orthoformate HC (OR
1)
3With trialkyl phosphite P (OR
2)
3Heating reflux reaction, low-boiling-point substance is removed in air distillation after the reacting by heating, makes (suberyl amido) methylenediphosphonate (MDP) with hydrochloric acid hydrolysis again, sees reaction formula (three).It is trialkyl phosphite that one of its raw material reaction thing has creatively adopted trivalent organophosphorus compounds.
Reaction formula (three):
R
1, R
2Each represents a low alkyl group.
Alkyl orthoformate HC (OR described in the inventive method
1)
3Can be trimethyl orthoformate or triethyl orthoformate, described trialkyl phosphite P (OR
2)
3Can be triisopropyl phosphite or triethyl-phosphite.
Heating reflux reaction described in the inventive method, the mole proportioning of its reactant is that the mole proportioning of cycloheptylamine and alkyl orthoformate and trialkyl phosphite is 1: 1.0～1.2: 2.0～2.5, Heating temperature is for keeping the temperature of backflow, look raw materials used difference, the reflux temperature also can be variant.The heating reflux reaction time is 2～2.5 hours.Reflux finishes, and low-boiling-point substance is removed in air distillation.During hydrochloric acid hydrolysis, the hydrochloric acid of Jia Yue and reaction-ure mixture equivalent (W/W or V/V) refluxed 1～1.5 hour.Hydrolysis refluxes and finishes, and air distillation concentrates, and adds methyl alcohol-acetone mixed solution precipitating after concentrating, and separates out crystal, in 60 ℃ of dryings, gets the white crystals product, mp231-233 ℃.
Advantage of the present invention is easy and simple to handle, replaces dialkyl phosphite (pentavalent phosphorus) to participate in reaction with trialkyl phosphite (three valent phosphors), and resultant need not post to be separated, the reaction conditions gentleness, the reflux time shortens during reaction, removes low-boiling-point substance and only needs air distillation, also cools off without ice bath.Steady quality, yield height, cost are low, and facility investment is few, is applicable to big industrial production.
Embodiment
Embodiment 1
Cycloheptylamine 56.6g (0.5mol), triethyl orthoformate 81.5g (0.55mol), triisopropyl phosphite 218.6g (1.05mol) add reaction flask, reflux 2 hours, low-boiling-point substance is removed in air distillation, add hydrochloric acid 300ml, refluxed 1 hour, add methyl alcohol-acetone mixed solution after concentrating, separate out crystal, drying, product mp231-233 ℃, yield 85.0%.
Embodiment 2
Press embodiment 1 same procedure, but replace triisopropyl phosphite, yield 75.1% with triethyl-phosphite.
Embodiment 3
Press embodiment 1 same procedure, but replace triethyl orthoformate, yield 56.8% with trimethyl orthoformate.1. ultimate analysis (C
8H
19NO
6P
2)
C H N calculated value (%) 33.46 6.67 4.87 measured values (%) 33.21 7.02 4.742. mass spectrums (FAB): 288 (M
++ H, 70%) 3. infrared spectra (IR): 3421 (N-H), 2956,2867 (C-H) 4.
1The H nuclear magnetic resonance spectrum (
1H-NMR): D
2O is a solvent
δ 1.50-1.75,10H (2Hc, 4Hd, 4He) δ 2.11-2.15,2H (2Hc) δ 3.58,1H (Hb) δ 3.69,1H (Ha)
Claims (5)
1. the preparation method of one kind (suberyl amido) methylenediphosphonate (MDP) is characterized in that this method adopts cycloheptylamine and alkyl orthoformate HC (OR
1)
3With trialkyl phosphite P (OR
2)
3Heating reflux reaction, low-boiling-point substance is removed in air distillation after the reacting by heating, makes (suberyl amido) methylenediphosphonate (MDP), R with hydrochloric acid hydrolysis again
1, R
2Each represents a low alkyl group.
2. by the preparation method of claim 1 described a kind of (suberyl amido) methylenediphosphonate (MDP), it is characterized in that described alkyl orthoformate HC (OR
1)
3Can be trimethyl orthoformate or triethyl orthoformate; Described trialkyl phosphite P (OR
2)
3Can be triisopropyl phosphite or triethyl-phosphite.
3. press the preparation method of claim 1 described a kind of (suberyl amido) methylenediphosphonate (MDP), it is characterized in that described heating reflux reaction, the mole proportioning of cycloheptylamine and alkyl orthoformate and trialkyl phosphite is 1: 1.0～1.2: 2.0～2.5, Heating temperature is for keeping the temperature of backflow, and the heating reflux reaction time is 2～2.5 hours.
4. by the preparation method of claim 1 described a kind of (suberyl amido) methylenediphosphonate (MDP), it is characterized in that describedly when using hydrochloric acid hydrolysis, the hydrochloric acid of Jia Yue and reaction-ure mixture equivalent (W/W or V/V) refluxed 1～1.5 hour.
5. by the preparation method of claim 1 described a kind of (suberyl amido) methylenediphosphonate (MDP), it is characterized in that the hydrolysis backflow finishes, air distillation concentrates, add methyl alcohol-acetone mixed solution precipitating after concentrating, separate out crystal, in 60 ℃ of dryings, get the white crystals product, mp231-233 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021125619A CN1142168C (en) | 2002-01-16 | 2002-01-16 | Process for preparing (cycloheptylamino) methylene biphosphonic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021125619A CN1142168C (en) | 2002-01-16 | 2002-01-16 | Process for preparing (cycloheptylamino) methylene biphosphonic acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1363556A true CN1363556A (en) | 2002-08-14 |
| CN1142168C CN1142168C (en) | 2004-03-17 |
Family
ID=4742100
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB021125619A Expired - Lifetime CN1142168C (en) | 2002-01-16 | 2002-01-16 | Process for preparing (cycloheptylamino) methylene biphosphonic acid |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1142168C (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102124016A (en) * | 2008-07-11 | 2011-07-13 | 斯索恩有限公司 | Process for making 1-hydroxyalkylidene-1, 1-biphosphonic acids |
| CN105061502A (en) * | 2015-08-05 | 2015-11-18 | 浙江理工大学 | Synthesis method of bis(2-carboxylethyl)phosphonic acid |
-
2002
- 2002-01-16 CN CNB021125619A patent/CN1142168C/en not_active Expired - Lifetime
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102124016A (en) * | 2008-07-11 | 2011-07-13 | 斯索恩有限公司 | Process for making 1-hydroxyalkylidene-1, 1-biphosphonic acids |
| CN105061502A (en) * | 2015-08-05 | 2015-11-18 | 浙江理工大学 | Synthesis method of bis(2-carboxylethyl)phosphonic acid |
| CN105061502B (en) * | 2015-08-05 | 2017-05-10 | 浙江理工大学 | Synthesis method of bis(2-carboxylethyl)phosphonic acid |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1142168C (en) | 2004-03-17 |
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