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WO1998055487A1 - Composes de phosphate - Google Patents

Composes de phosphate Download PDF

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Publication number
WO1998055487A1
WO1998055487A1 PCT/GB1998/001644 GB9801644W WO9855487A1 WO 1998055487 A1 WO1998055487 A1 WO 1998055487A1 GB 9801644 W GB9801644 W GB 9801644W WO 9855487 A1 WO9855487 A1 WO 9855487A1
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WO
WIPO (PCT)
Prior art keywords
group
groups
hydrogen
formula
compound
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.)
Ceased
Application number
PCT/GB1998/001644
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English (en)
Inventor
Richard Neil Templar Freeman
Simon William Leppard
Jeremy Colin Russell
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abbott Vascular Devices Ltd
Original Assignee
Biocompatibles Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Biocompatibles Ltd filed Critical Biocompatibles Ltd
Priority to AU77812/98A priority Critical patent/AU7781298A/en
Publication of WO1998055487A1 publication Critical patent/WO1998055487A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F30/00—Homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and containing phosphorus, selenium, tellurium or a metal
    • C08F30/02—Homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and containing phosphorus, selenium, tellurium or a metal containing phosphorus
    • 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
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/113—Esters of phosphoric acids with unsaturated acyclic alcohols
    • 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
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/117—Esters of phosphoric acids with cycloaliphatic alcohols
    • 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
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/6574—Esters of oxyacids of phosphorus
    • C07F9/65742—Esters of oxyacids of phosphorus non-condensed with carbocyclic rings or heterocyclic rings or ring systems

Definitions

  • the present invention relates to the synthesis of certain phosphate compounds which are useful as monomers for polymerisation and/or as intermediates for producing novel reactive compounds bearing phosphate groups.
  • reagents which are useful for derivatising preformed surfaces, for instance of polymeric substrates, to introduce PC groups.
  • Such reagents are generally mono functional, that is each reagent molecule includes a single PC group and a single reactive group. Examples of some such reagents are described in EP-A-0157469, EP-A-0515895 and EP-A-0556216 (WO-A-9207858).
  • EP-A- 0515895 reagents which are capable of reacting with amino groups at surfaces to give amine linkages are described.
  • EP-A-0556216 compounds which react with surface amino, hydroxyl and carboxylic groups include activated amine groups.
  • WO-A-9301221 we described copolymers of ethylenically unsaturated PC group containing monomers and copolymerisable comonomers selected so as to give suitable surface binding characteristics.
  • One class of comonomers includes a reactive group by which covalent bonding to an underlying surface may be carried out. Examples of covalent reactive groups include an aldehyde group.
  • covalent reactive groups include an aldehyde group.
  • Several techniques have been described for synthesising phosphoryl choline derivatives and analogues thereof. The route we have used involves the reaction of an alcohol with 2-chloro-2-oxo-l,3,2-dioxaphospholane (CCP) followed by a ring opening amination of the phospholane.
  • CCP 2-chloro-2-oxo-l,3,2-dioxaphospholane
  • PC may have significant benefits in extending the life and reducing calcification of tissue valves, although the means by which PC had been incorporated into such heart valve was not disclosed.
  • Monomers for use in forming condensation polymers such as polyesters and polyurethanes have been described.
  • monomers comprising two hydroxyl groups are used to react with di-isocyanates and dicarboxylic acids respectively to form polyurethanes and polyesters.
  • Biological tissues can be "fixed" by allowing them to soak for some minutes in a dilute solution of a dialdehyde, usually glutaraldehyde.
  • the glutaraldehyde is used to cross link proteins by their amine groups.
  • Other dialdehydes having even numbers of carbon atoms between the CHO groups have been disclosed in US-A-5429797. Lysine residues in the proteins are the most common source of these amine groups.
  • the aldehyde and amine undergo a condensation reaction to form an imine with the subsequent loss of water. Further details of the reactions taking place are described by Cheung, D.T., et al in Connective Tissue Res. (1982) 10, 187-199.
  • the major constituent of bioprosthetic implants is the protein collagen.
  • collagen is cross-linked with glutaraldehyde. The problem is that, after implantation, calcification onto the implant gradually occurs, rendering it necessary to replace the implant.
  • the present inventors have established that a PC derivative having two aldehyde groups or precursors to aldehyde groups, such as gem diols, hemiacetals and acetals, is useful to replace glutaraldehyde in tissue fixing.
  • the present invention provides an intermediate used in the synthesis of such a compound.
  • the intermediate has other uses as a reagent for producing other difunctional PC derivatives and as a radical polymerisable compound.
  • the invention also provides a process for producing the novel compound.
  • R 1 is CR 12 2 in which each R 12 is independently selected from hydrogen and a C 1 - 4 -alkyl groups, and
  • R 6 may together form a group selected from Cj. 5 alkylene and C 2 . 5 alkylidene groups in which the alkylene or alkylidene groups may be substituted by a hydroxy or a protected hydroxyl group or a group of formula III ;
  • R 7 is selected from hydrogen and C._ 4 alkyl groups
  • R 8 is a bond or a C M alkylene
  • R 9 is a bond or a group C(R 10 )R n ; each group R 10 is selected from hydrogen and C,- 4 alkyl groups; each group R n is selected from hydrogen and C j _ 4 alkyl groups or two groups R u may form a C 5 alkylene group; and n is 1-4; is reacted in an aprotic polar solvent with an amine of the formula II NR 13 2 R 14 (II) in which each R 13 is H or Me, and R 14 is selected from H and C-. 24 alkyl, . ⁇ hydroxyalkyl, C 4 . 24 -cycloalkyl, C 7 . 24 aralkyl, C 6 . 24 aryl (including alkaryl) to produce a compound of the Formula IN
  • R 4' , R 5' and R 6' are the same as groups R 4 , R 5 and R 6 , respectively, of the compound of the formula I or, where a group R 6 included a group of formula III that group R 6' is the same as the respective group R 6 except that the group of formula III is replaced by a group of formula N
  • R 9 to R 11 are the same as in the compound of the formula I.
  • R 13 and R 14 are the same as in the amine compound of the formula II.
  • the dioxaphospho ring of the compound of the formula I is preferably attached through a phosphate ester bound to the residue of a secondary alcohol, that is R 8 is preferably a bond.
  • the process is of particular value for producing intermediates in which the ethylenically unsaturated bond(s) of the ammonium phosphate ester compound of the formula IV are further derivatised, for instance by oxidation to form a carbonyl- containing groups C(O)R 3 .
  • such compounds are aldehydes, and hence the groups R 3 are preferably hydrogen.
  • the dioxaphospholane compound of the formula I is preferably symmetrical.
  • R 4 is R 5 CR 6 2 and both R 5, s are the same.
  • each R 5 is a bond or CR 6 2 , that is a group (CR 6 2 ) n in which n is 1 and the groups CR 6 2 are the same.
  • dialdehyde end product formed from the product of the process of the present invention may be susceptible to an internal aldol condensation reaction, which is undesirable.
  • R 6 attached to each of the carbon atoms joined to the group R 1 and R 2 together to represent a methylene group.
  • the alcohol residue is cyclic, that is R 1 and R 2 together are CR 3 .
  • the compound of the formula I can be represented as the general formula NI
  • the compound is achiral, that is R 4 is R 5 CR 6 2 and both groups R 5 are identical and both groups CR 6 2 are identical.
  • the alcohol residue is a cyclic, that is the compound of the formula I is an alkadiene compound.
  • Such compounds can be represented by the general formula NTJ
  • the compound is achiral.
  • R 4 is R 5 CR 6 2 and both groups R 5 are the same.
  • the two groups CR 12 2 are the same. More preferably each R 12 is methyl or, most preferably, hydrogen.
  • R 7 is preferably a methyl group or, more preferably hydrogen.
  • the process of the present invention may be of value for producing products having more than one group of formula N, but is of most use where the product has only one such group. Accordingly it is preferred that no group R 6 contains a group of formula III. It is also preferred that R 6 not include a hydroxyl or protected hydroxyl group.
  • Each R 6 is thus preferably C M -alkyl, for instance methyl, or more preferably, hydrogen, or alternatively that two groups R 6 together form a C ⁇ alkylene group, preferably whereby the two groups R 6 and the carbon atoms to which they are attached and any carbon atom to which those carbon atoms are in turn both attached (i.e. where the two groups R 6 are attached to next adjacent carbon atoms) form a 5- or 6- membered ring.
  • Such compounds, also where R 1 and R 2 together are CR 3 are polycycloalkyl compounds.
  • each group R 11 is selected from hydrogen and C M alkyl, more preferable methyl, most preferably hydrogen.
  • a preferred embodiment of process includes a first step for producing a compound of the formula I, in which an alcohol of the general formula NIII
  • R 1 to R 3 , R 7 and R 8 are the same as in the compound of the formula I and
  • R 4" to R 6" are the same as the groups R 4 to R 6 , respectively, of the compound of the formula I, provided that where any groups R 6 comprises a group of formula III, the corresponding group R 6" comprises a hydroxyl group in place of the group of formula III, is reacted with a halophospholane of the general formula IX
  • R 9 to R 11 are the same as the groups R 9 to R 11 of the compound of the formula I;
  • Hal is a halogen atom.
  • Hal is preferably chlorine, but may alternatively represent bromine or iodine.
  • the product of the process of the first aspect of the invention is believed to be novel and compounds of the general formula IN forms a further (second) aspect of the invention. Some of the compounds of the general formula I are also believed to be novel compounds and form the third aspect of the present invention.
  • R 21 is CR 24 2 in which each R 24 is independently selected from hydrogen and C M alkyl groups;
  • R 7 to R 11 are as defined in relation to the compound of the formula I.
  • the groups R 23 are hydrogen.
  • both groups CR 26 2 are identical.
  • the groups R 26 are identical. More preferably all groups R 26 are hydrogen.
  • two groups R 26 together are C,. 5 alkylene, preferably whereby a 5 or 6 membered ring is formed with the carbon atoms to which they are attached and with the carbon atom to which those two carbon atoms are in turn attached (ie where the two R 26 groups forming the alkylene are attached to different carbon atoms).
  • Preferred groups R 24 are methyl, or more preferably hydrogen. Preferably in a compound having two groups CR 24 2 , the groups CR 2 2 are identical.
  • One embodiment of this aspect of the invention is a cyclopentene compound of the general formula XI
  • Another embodiment is a 1,6-heptadiene compound of the general formula XII
  • the compounds of the Formula IV may be used as monomers in polymerisation, either alone, or, preferably, along with copolymerisable unsaturated comonomers.
  • the comonomer may be an ethylenically unsaturated comonomer for instance any of those mentioned in our publication WO- A-9301221 , especially the acrylic comonomers.
  • Cycloalkene compounds of the formula VI may alternatively be polymerised by ring opening metathesis polymerisation usually with cyclic alkene comonomers, which may be cyclopentene, cyclohexene or norbornene derivatives. Such polymerisations are described in J. Molecular Catalysis A. Chemical, 115(1997) 85-94.
  • the ring opening reaction of the compound of the formula I with the amine of the formula II is preferably carried out under anhydrous conditions, to avoid production of hydrolytically ring opened by-product.
  • the solvent may be selected from the same solvents as that used for the first step. For a two step process, preferably the solvents used in the two steps are the same and the compound of the formula I is not isolated from the solvent used for the first step before the step of reacting with the amine is carried out.
  • the solvent is preferably a nitrile, most preferably acetonitrile.
  • the reaction of the alcohol compounds VII with the phospholane IX is preferably carried out in the presence of a tertiary amine base to assist removal of hydrogen halide co-product from the reaction mixture as a precipitate.
  • a tertiary amine base is triethylamine.
  • the compound of the Formula IN may be recovered from the product mixture by removal of the solvents and may be purified by known techniques.
  • the alcohols of the formula NIII are generally known compounds.
  • the two step process of the present invention may consequently use as starting materials commercially available alcohols of the formula NIII. Where the alcohol is not readily available it may be synthesised in one or more preliminary steps. The process of the present may include such preliminary steps.
  • a Grignard reagent is formed by reacting magnesium with allyl bromide and is reacted with an ester R 7 COOR 15 where R 15 is C j . 6 alkyl, preferably ethyl, in the following reaction scheme.
  • step 1.3 The steps prior to step 1.3 are described by Crandal, JK et al in J. Org. Chem. (1968) 33, 423.
  • 1.1-1.2 Synthesis of 3-Cvclopenten-l-ol 1.1
  • cyclopentadiene 57.8g, 0.87mole
  • sodium carbonate 400g
  • dichloromethane 1000ml
  • peracetic acid 168ml, 40% in acetic acid
  • pre-treated with sodium acetate 0.2g
  • Ir (KBr smear) 3401, 2959, 2510, 1653, 1483, 1220, 991, 769, 668, 510.
  • OPC is a group of formula V in which R 9 is a bond, each R 10 and each R 11 is hydrogen and each R 13 and R 14 are methyl.
  • Trimethylamine 13.17 g, 0.223 mol was added and the solution heated at 50 °C overnight in a closed system. The solution was cooled, degassed, and the solution decanted. The solvent was evaporated and the residue partitioned between H 2 O (150 ml) and dichloromethane [DCM] (150 ml). The aqueous layer was washed with DCM (150 ml), separated and evaporated. The residue was washed with acetone (2x 150 ml) and stored in acetone (100 ml) overnight. The acetone layer was evaporated to leave a solid residue. The solid residue was identified as the product: ⁇ NMR (400 MHz, D 2 O) ⁇ complex spectra.
  • Trimethylamine (3.10 g, 0.053 mol) was added and the solution heated at 50 °C overnight in a closed system. The solution was cooled, degassed and the solution decanted. The solvent was evaporated and the residue partitioned between H 2 O (125 ml) and ether [Et 2 O] (130 ml). The aqueous layer washed with Et 2 O (130 ml), separated and evaporated. The residue was identified as a phosphorous species, but without the dialkene. ⁇ NMR (400 MHz, D 2 O) ⁇ complex spectra. 13 C NMR (50.1 MHz, D 2 O) ⁇ 54.0 (M- NCH ⁇ , 55.0 (CH 2 NMe 3 ), 62.2 (CH 2 OPO).
  • the solvent was decanted off and the precipitate was redissolved in methanol (15 ml) and chloroform (20 ml).
  • the polymer solution was reprecipitated in acetone (350 ml).
  • the polymer was identified as: ⁇ NMR (400 MHz, CD 3 OD/CDCl 3 ) complex spectra.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Polymers & Plastics (AREA)

Abstract

Composé représenté par la formule (IV) dans laquelle R1 et R2 représentent ensemble CR3, ce qui constitue, dans ce cas, un noyau mono-insaturé, ou R1 représente CR122 (normalement CH2) et R2 représente CR3=CR122 (normalement CH=CH2), ce qui constitue, dans ce cas, un composé cyclique di-insaturé, et dont on effectue la synthèse par réaction d'un alcool (VIII) avec un dioxaphospholane, suivie par une amination d'ouverture de noyau avec une amine NR132R14. On peut utiliser ce composé en tant que monomère dans une réaction de polymérisation ou on peut en effectuer la réaction par oxydation de la liaison ou des liaisons C=C, par exemple, par oxydation, dans le but d'obtenir d'autres composés utiles.
PCT/GB1998/001644 1997-06-04 1998-06-04 Composes de phosphate Ceased WO1998055487A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU77812/98A AU7781298A (en) 1997-06-04 1998-06-04 Phosphate compounds

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP97303847 1997-06-04
EP97303847.4 1997-06-04

Publications (1)

Publication Number Publication Date
WO1998055487A1 true WO1998055487A1 (fr) 1998-12-10

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PCT/GB1998/001644 Ceased WO1998055487A1 (fr) 1997-06-04 1998-06-04 Composes de phosphate

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AU (1) AU7781298A (fr)
WO (1) WO1998055487A1 (fr)
ZA (1) ZA984837B (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009158461A1 (fr) * 2008-06-25 2009-12-30 Boston Scientific Scimed, Inc. Copolymères médicaux
US7687483B2 (en) * 2000-08-03 2010-03-30 D-Pharm Ltd. Derivatives of branch-chain lipophilic molecular and uses thereof
US20120215006A1 (en) * 2009-11-05 2012-08-23 Merck Patents Gessellschaft Mit Beschrankter Haftung Synthesis of phosphoric esters

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0157469A1 (fr) * 1984-01-20 1985-10-09 Biocompatibles Ltd. Esters de l'acide phosphorique, leur préparation et leur utilisation pour la préparation de surfaces biocompatibles
WO1992007858A1 (fr) * 1990-11-05 1992-05-14 Biocompatibles Limited Esters d'acide phosphorique et leur utilisation dans la preparation de surfaces biocompatibles
WO1993001221A1 (fr) * 1991-07-05 1993-01-21 Biocompatibles Limited Revetements polymeres de surfaces

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0157469A1 (fr) * 1984-01-20 1985-10-09 Biocompatibles Ltd. Esters de l'acide phosphorique, leur préparation et leur utilisation pour la préparation de surfaces biocompatibles
WO1992007858A1 (fr) * 1990-11-05 1992-05-14 Biocompatibles Limited Esters d'acide phosphorique et leur utilisation dans la preparation de surfaces biocompatibles
WO1993001221A1 (fr) * 1991-07-05 1993-01-21 Biocompatibles Limited Revetements polymeres de surfaces

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
D. M. BROWN: "Hydrolysis of hydroxyalkyl phosphate esters: the epoxide route.", JOURNAL OF THE CHEMICAL SOCIETY., 1965, LETCHWORTH GB, pages 6547 - 6558, XP002045715 *
NGUYEN THANH THUONG: "Nouvelle méthode de préparation des dérivés monosubstitués de l'acide orthophosphorique par action du cyanure de sodium sur les dioxaphospholannes-1.3.2.", COMPTES RENDUS DE L'ACADEMIE DES SCIENCES : SERIE GENERALE. LA VIE DES SCIENCES., no. 19, - 6 November 1972 (1972-11-06), MONTREUIL FR, pages 11251127, XP002045713 *
RAGHUPATHY SARMA: "Conformation of the choline phosphate zwitterion.", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY., vol. 100, no. 14, 1978, DC US, pages 4453 - 4458, XP002045714 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7687483B2 (en) * 2000-08-03 2010-03-30 D-Pharm Ltd. Derivatives of branch-chain lipophilic molecular and uses thereof
WO2009158461A1 (fr) * 2008-06-25 2009-12-30 Boston Scientific Scimed, Inc. Copolymères médicaux
US8187623B2 (en) 2008-06-25 2012-05-29 Boston Scientific Scimed, Inc. Medical copolymers
US20120215006A1 (en) * 2009-11-05 2012-08-23 Merck Patents Gessellschaft Mit Beschrankter Haftung Synthesis of phosphoric esters
JP2013510102A (ja) * 2009-11-05 2013-03-21 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング リン酸エステルの合成
US8940907B2 (en) * 2009-11-05 2015-01-27 Merck Patent Gmbh Synthesis of phosphoric esters

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Publication number Publication date
ZA984837B (en) 1999-06-04
AU7781298A (en) 1998-12-21

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