SA04250347B1 - Methods for the preparation of [_2](8,9_dioxo_2,6_diaza_bicyclo[5,2,0]non_1(7)_en_2_yl]ethyl]phosphonic acid and its derived esters - Google Patents

Abstract

Abstract: The present invention provides methods for the preparation of {2-(8,9-dioxo-2,6-dineaza-bicyclo[5,2,0]-N-1-(7)-en-2-yl]ethyl } phosphonic acid [2-((8,9)-dioxo-2,6-2- diaza- bicycle [5.2.0]-non-1(7)-en-2- esteryl)ethyl]phosphonic acid and esters derived from it .

Description

Y

- [0;7 co]aza -bicyclo el -exo AEA 0([-7] Methods for the preparation of (-yen-"-yl[ethyl]phosphonic acid and its derived esters 1(- 1-Noun

Methods for the preparation of [2-[(8,9)-dioxo-2,6-diazabicyclo [5.2.0]-non-1(7)-en-2-yl]ethyl] phosphonic acid and esters thereof Al-Kamil Background of the invention [2-((8,9)-dioxo-2,6-diaza- The present invention concerns methods for the preparation of bicyclo-esters and esters[S5.2.0]-non-1 derived therefrom. (7)-en-2-yl)ethyl]phosphonic acid glutamic acid Exciters, for example, glutamic acid amino acids Amino acids have been shown to represent important neurotransmitters (Johnson; R.L.; Kuerer; J.F. ; Koerner, J.F., J. Med. Chem. Medicinal chemistry, which in an increase of sedimentation in a sequence of events leads to neurological damage after ischemia; dy aan; Choi, E. W, Trends in Brain Science (Choi; EW amino acid is an important subspecies of the 0 amino acid receptor) P ¢ VY lectin -methyl-0 N ; Which is characterized as a selective antagonist for the excitable NMDA-acid is the receptor 0 by blocking the effect of the internal antagonist by means of . (NMDA) N-methyl-D-aspartic acid -4-(3-phosphonopropyl-2-piperazinecarboxylic ~~ NMDA= ALE wa Ad et al. have been shown to inhibit ischemic damage in the thorax. Also post C (CPP) acid; YEO-induced convulsions (VAM.l.©; Brain Research; et al., in rats (Lehmann J. et al.; CPP Journal) by - 1740/8 is inhibited by 0 experimental therapeutic mother M6 Lehmann, J. al, Pharmacol. Exp. Pharmacology has shown that it is CPP, for example, NMDA finally «the competitive antibody. 1-Leneph-1-Lethium-1 (MPTP) inhibits Parkinson's-like symptoms induced by the in(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) cross-linked hydropyridine. 1 “Ye Ye 144) Turski, L. et al. Nature Mice (Turski L. et al.; Nature (Nature) ve v ¢ are suitable for the treatment of epilepsy. For these reasons, NMDA receptor antagonists EVE « Engelsen, B., Acta Neurol Scand Stroke (Engelsen B; Acta Neurol Scand. Neurodegenerative diseases, for example, Alzheimer's disease) FRY 0 VE VAAN Trends in Neurosciences; ¢ Maragos, 117.1 . ©] al, Maragos W.F. For the Ju receptor, known as Chemical compounds, separate phosphonic acid containing 41 moths “and dead” - adsorbed + E and the activities of phosphonic acid 2-amino-5- decorated as an ssid via A variety of spacer units, for example, Watkins, J. C.; Evans, R. H., Annu. Rev. Pharmacol. Toxicol. Saturated. The largest examples are carbon, which contains a carbon chain (110 71 VAAN) that contains elements that improve structural (structural) rigidity and therefore strength; is complex; cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid 0 + includes (see above).

Lehman, J. et al, J. ¢ Pharmacological Journal (YAY0O— CGS) 0 (E)-2-amino-4-methyl-5- 5 ¢ (10 ¢ Y£1 ¢ YAAA Therapeutic Experimental Pharmacol (Schmutz M. et al.; Abs. Suss. (YYA£4— CGP) phosphono-3- pentenoic acid } compound. (ANE 06 YAAA) (Schmutz, M. et al., Abs. Soc. Neurosci Neurosci. NMDA is an antagonist {2-[(8,9)-dioxo-2,6-diaza-bicyclo[5.2.0]-non-1(7)-en-yl] Ethyl-10700/- induced mortality is inhibited in vivo and is useful as anticonvulsant agents and neuroprotectants in states involving excitatory release See US Patent No. amino acids Amino acids incorporated herein are entirely attested. General Description of the Invention" 0.76

p 8 I HN N TN f- OH J OH I : and esters derived from it have formula 17 : 8 I HN N TN | — OR 1 J 0 Ro ° 11 where Ry and Ro separately are a 1-1 carbon Crs alkyl or a 1-1 carbon haloalkyl haloalkyl . In some examples, the methods involve an interaction; in a solvent; Compound of formula 11 : 0 a NTN NS > OR 5 01 I with a compound of formula 11 27 [Qq Qo Y.q¢ I]

0 where © and 0 are each OH ; halogen or OX;; where <0 is an alkyl of 1-1 carbon alkyl .© ; A haloalkyl is made up of 1-1 carbon atoms haloalkyl© or aryl ; Said solvent has the formula ©1107; For a period of time and through effective conditions for the production of the said compound of formula 17.

° And in some favorite examples; © and ,© are the same. and in some CIB (when © , and Qp have the form OX); Hence, the 16th part of the solvent is not symmetrical as for the D part of:9 and:0.

And in some examples; The methods additionally include the step of hydrolysing the said compound of formula 17 to provide the compound of formula 1: - Ye. 0 0 I Lo J Non L and in some examples; The compound according to the formula [1] is prepared by the reaction of the compound of formula V or formula 71: E 8 C 00 Nor, NT Non, C VI 7 vo, where X is a leaving group; with GEO) .1,3-diaminopropane and in some examples of methods discussed; Ry and Ry separately are methyl “ethyl” propyl (eg n-propyl gabe; or isopropyl Y.4q¢

. (isopropyl; or butyl) for example; n-butyl; Tert-butyl (t-butyl). In some examples of the methods discussed, Ry and Rp are both ethyl. In additional examples, Ry and 82 are the same. In some other examples, the solvent is methanol methanol or ethanol In some examples old the solvent is methanol © .methanol In some examples Qu and , each are OH In Cea examples : and 0: each is a halogen In other examples, the © and :© are each an OX, since 76 is an alkyl composed of 1-1 carbon atoms, preferably methyl ethyl Ji; n-propyl » isopropyl n-butyl + or t-butyl tert-butyl 0 and in some favorite examples « .© and :© are OCH,CH; . In additional preferred examples: Qu and ©: each are 0011:013; the solvent is .methanol; For methanol 0, and in some other examples, both 0 and 0 are OX, where Xo is an alkylhalo, and in other examples, © and :0 are 06, where that Xp is an aryl and in some examples 0 is ,© and :0 (DLAI; And in other examples; The ,9 and :0 . two different | 0; Where * is isotropic. and in OX and in some examples; The © and :© are each ethyl « methyl and J18 each separately is Ry methyl Some other examples; the

OX; The two mentioned are Q; Both: © and butyl or butyl « propyl - propyl ethyl ; isopropyl nopropyl 16, methyl; ethyl; ordinary propyl The solvent used is t-butyl; or n-butyl tert-butyl; "Normal butyl" isopropyl "©

Y.q¢

Y

and j8 separately is Ry and in other examples; the . ethanol Methanol or ethanol where © , is OX; Michelle or Ethel; Both © and :© mentioned are 8, and in other examples; the . ethyl methanol; The solvent used is methanol; OH and ©: are Qi each separately is methyl; or ethyl; Both Rp and .ethanol and the solvent used is methanol or ethanol © separately is methyl or JSR and Ry and in some additional examples ; the ;chlor; In preference to chlorine halogen and 0. mentioned is Qu ethyl halogen; Each of, or ethanol [recombinant. methanol, and the solvent used is methanol. halo is halo X, and in some examples, brom or chlorine is chlorine X, so 0 and in other examples 01 ;7-Diaminopropane 1 of molar and in some examples; The molar ratio represents the mentioned VI to the mentioned compound of formula 57 or formula 1,3-diaminopropane; preferably close to at least © : 1; With greater preference it is rounded to 1 : 7 at least by approximately . 0: ©; and with greater preference it approximates at least 1 : 4 less than and in some examples; The reaction of the compounds of formulas [1 and 117] takes place at a temperature of Vo of 50 °C, a temperature lower than the boiling point of the solvent; approximately 10 to 00 degrees Celsius; with a preference for a temperature of approximately Vie Celsius to approximately 1°C to approximately 15°C ; With greater preference at a temperature of approximately . degrees Celsius, and in some examples; Where the formula 17 compound is prepared by Ye; the V with the compound of formula 1,3-diaminopropane SEY the reaction of the compound of formula [1] combines with a greater yield of approximately 7560; Preferably with greater productivity than . 7160 approx

SET and in some examples; The reaction of the mentioned compound of formula 17 and Celsius is approximately 10 ©? Aminopropane 1,3-018001000006 at a temperature of about L

A fr °C to approximately 10 °C; and with a preference of approximately O00 of Yo to approximately 19 °C; with greater preference at Te about 10 °C; and with greater preference at approximately C. ° and in some examples where the compound of Formula I is prepared by SEY Jeli (1,3-diaminopropane) with the compound of Formula VI; The compound of formula [1] combines with a greater yield of approximately 790 and with a greater preference of approximately 7958. And in some examples; The reaction of the compound of formula VI and HET is 1,3-diaminopropane | 0 is carried out at a temperature of approximately 10-10°C; with a preference of approximately £0,710°C; and with greater preference from approximately 40-701 degrees Celsius. And in some examples of each of the previous methods; A compound of formula [1] and a compound of formula I react in substantially equal molar amounts. M. The present invention further provides a product prepared by the present process +- a (Jeli; in a solvent; a compound of the formula [1: 0 arum 205 INT N Bn II | wherein: 18 and 82 are each separately an alkyl of 1-3 carbon alkyl:© or a haloalkyl of 1-1 carbon atom haloalkyl 06 ; with a compound according to the formula 0 [11 : ] 90,6 Qj 22

Where Qs Q individually is 011 ; Halogen + or 030; Where © is an alkyl of 1-1 carbon alkyl p ; A haloalkyl is made of 1-1 carbon atoms cis haloalkyl or aryl ; The said solvent has the formula HOX, ; > For a period of time and through effective conditions to produce a compound according to formula 17: 0 0 I and 05 J \

117 3 b) hydrolyze the said compound of formula 17 to provide a compound of formula [:

ْ : 0 I OH —_ | Thief and HN N J Nou \ IL ve and in some examples; the product contains at least one compound selected from formulas X 3 IX « VII VII : Yoqté

1 0. 0 0 1 0 0 9 0 0 0

J HO 01 0 01 HO OH vil VIII IX X; Halo Alkyl © alkyl carbon atom 1-6 is an alkyl component of x, where in preferred examples; the . aryl or aryl Cre haloalkyl carbon atom 1-1 composed of and, for example, . X or IX ¢ 7111; VIT product contains at least one of the formulations

CTY less than approximately IX preferred; the product contains a compound of formula less than approximately 720.06; or less than approximately 70.01 by weight. : 17 The present invention further provides compositions comprising a compound of formula 0 0 0

J OR;

Iv carbon atom 1-6 apart is an alkyl of JSR, where , 8 , and haloalkyl carbon atom 1-1; or haloalkyl composed of ©. alkyl 0 and at least one compound selected from CH VII ¢ VII ¢ T1 and 6L ; Whereas, 75 is an alkyl of 1-1 carbon alkyl .© ; A haloalkyl is composed of 1-1 haloalkyl carbon atoms or aryls. In some examples, 16 is ethyl. And in some examples; Ry and Ry are each ethyl Jf, and in some examples; The present invention provides a composition comprising a compound of formula M 1 and at least one compound of formulas X SIX » VII ¢ VIT wherein Xi is 7.4

1 corn 1-1 mtr; A haloalkyl composed of an alkyl carbon atom 1-3 is an alkyl composed of or an aryl. And in some examples; At least one compound, Cris haloalkyl carbon, is present in the denatured formation containing 7 STK « VII 717 selected from the formulas, so 0 compounds from formula 1 have an amount less than approximately 750 by weight. In additional examples, the composition includes a compound of formula 711 or 6. And in additional examples; The composition includes © . VIL contains a compound of the formula (Detailed description) 2-] (8,9)-dioxo-2,6-diaza-bicyclo } Provides methods for preparing Jal The invention. Esters and esters are derived from [5.2.0)-non-1(7)-en-2-yl)ethyl]phosphonic acid :3"-deca 0 The methods discussed here allow the preparation of the target compound without using without the use of nitrogen-protected ls 1,3-diaminocyclopropane [aminopropane].

IN or -

NON

0 ae 11

II with a compound of formula 0

Qq Qo mn -: Whereas

Jl a or © alkyl carbon atom 1-1 and separately is an alkyl composed of Ry and yen; haloalkyl carbon atom 1-1 composed of 1

VY

Xi ;, where OX) or « halogen - halogen OH separately is SQ and 1 1-1 ; Haloalkyl is composed of ©. alkyl carbon atom 1-1 is an alkyl composed of ; The solvent used contains the formula aryl or aryl Cris haloalkyl carbon atom; HOX; . 17 For a period of time and through effective conditions for the production of the said compound according to the formula 0 0 0

I

HN N TN | _—ORy button 11 is considered identical. and in Q and in some examples of the present invention; the alternatives © and ; .76 of the fraction of the solvent preferably OX; It includes the form Q and 0, Lovie additional examples. ©: From :9 and Xi The part is not italicized

Ji; separately is methylated sR; And in some examples; Van or butyl (isopropyl ¢ nepropyl ; (example; propyl propyl " ethyl

Ry and in some examples; the . (t-butyl tert-butyl « n-butyl ; Swe) butyl

JSR, sR; oli and 2 ; Each is either methyl or ethyl. And in some examples. An ethyl with II of formula N-(3-aminoethanephosphonic acid) ester Jeli Vo of formula 11 can be made with a squarate or a squarate derivative of a wide variety of solvents. And in some favorite examples; Alcohol solvents are generally referred to as non-examples. UL and especially those of the format .©1103; As described 0 to “ethanol JN!) methanol Specific solvents of choice include methanol and in some examples; The ratio of weight + butanol; and butanol isopropanol isopropanol 0

VY

520 to approximately 0 + 8060 to approximately 01 for solvent to compound of formula 1 Approx. to approximately 178 You to approximately 101 to approximately 700 ; approximately 001 approximately 0 . 000 of 7785; or approximate to the general reference to conducting the reaction of compounds of formula [1 and 11] using virtually equal molar amounts of each compound (i.e. including no more than 70 molar increments of one of the compounds in the reaction mixture); Thus, the benefit is provided by using smaller quantities of starting materials. It is also generally indicated that the reaction of compounds of formulas [1 and 117] be carried out using dilute reaction conditions.

I and in some examples; The reaction is carried out in terms of the ratio of the reagent (the amount of compounds of formulas 1 and 1).

Verve) to approximately 00 : 1 in grams) of total solvent (ml) ranging from approximately (Yer) to approximately 101:1; Approximate to 1:060 to 1:001 Approximate to 0.0560:11 Approximately not wishing to be surrounded by any particular theory; It is believed that the current methods La reduce the non-required reaction by taking in the characteristic of both the larger reactivity -(“-aminopropyl)aminoethanephosphonic acid ester N of the primary amino group of ci BY) and ¢ in some « N-(3-aminopropyl)aminoethanephosphonic acid ester Yo squarate esters, which will lead to the formation of alcohol squarate esters using an alcoholic solvent mixed with different reaction centers. The use of the appropriate solvent for this exchange with the squarate groups 0, and/or ,© can provide the additional benefit of conferring the use of compounds; And the active items in the site during the exchange of IT groups are squarates of the ester of the formula

III of the formula squarate ester or:© with the solvent. So ; The squarates of ester©s can contain a variety of groups at the :0 and :0 positions including the  alkoxy and oxygen groups eg the alkoxy halogens left over from the  halogens and in some preferred examples the + aryloxy And parts of the aryloxy ¢ haloalkoxy halo alkoxy ¢ ethoxy, especially 0'' ethoxy primal alkoxy is alkoxy Q the leaving group -butoxy or butoxy 0 isopropoxy isopropoxy Yo

Y¢ 01 degree Formulas [1 and 11] At a temperature near SUS the Vom reaction can be carried out below the boiling point of the solvent; than nearly 00 degrees Celsius; with a temperature preference of approximately 10-00°C; with greater preference. °C Ve at a temperature of approximately and in some examples; The reaction of compounds of formulas [1 and 11] can be carried out by simultaneous addition of solutions of two compounds in a solvent of formula 1107 to a vessel containing a preheated solvent. The reaction product with good yield and purity can be collected from the reaction mixture by any suitable technique; eg by recrystallization from a suitable solvent; Alagyl acetate .ethyl acetate is prepared by the reaction of phosphonates from TT and in some examples; the compound of formula 0:VI of formula phenyl phosphonate of formula 7; or phenyl phosphonate 0 0 0 cc M Non, No Non,

Vv VI aminopropane (EY) is a leaving group; With X where ?-1 it is useful to employ in excess of BN and in some + 1,3-diaminopropane

Pc in order to reduce the formation of diamine 1,3-diaminopropane diaminopropane 0 aminopropane SEY 1 substitution . So ; In preferred examples; The molar ratio of

CNY to the compound of formula © or of formula 71 approximated at least to 1,3-diaminopropane and preferably Vi 4 ; With greater preference it is at least approximated to 0: 7 and with greater preference it is at least approximated to

No has the greatest affinity for at least aminopropane (ET) with VI the reaction of compounds of formula No. 7 or 1 can be completed; Typically close to Mie in a wide temperature range; 1,3-diaminopropane °C or higher. And in some examples; the reaction of 10 °C to approximately 0 can be carried out at 1,3-diaminopropane (SET) and V compound of formula

Y.q¢

\o Celsius; and preferably from approximately 00°C to approximately 100°C heat; 11-39°C; With greater preference, it ranges from approximately 50 degrees Celsius. And in some examples; The Yee with greater preference ranges from approximately 1,3-diaminopropane SEY) the reaction of a compound of formula 1 and °C; with a preference of approximately 0010°C; 10-10 temperature ranges from approximately 0 . 40-71 °C ; With a preference greater than 11-46 and a preference greater than

SEY) and in some favorite examples; A compound of formula 7 or 171f is reacted by the addition of a compound of formula 7 or 1 to 1,3-diaminopropane (aminopropane ¢) in a solvent representing (preferably 1,3-diaminopropane (SEY) solution from but without specifying; alcoholic solvent. Suitable solvents are those of formula 01 methylmethyl Daa as described above. Suitable solvents include primary alcohols; ¢ 1106 with butanol and isopropanol + ethanol being the most preferred. And in some examples; The weight ratio (eg; g / g) of approximately 01 is approximately 1,3-diaminopropane 7-diaminopropane 1 the solvent to

CAYO mf or near Yee approx 700-71 m 8000; Appropriate technology; For example by means of AJ chromatography the product of the reaction can be purified by means of silica gel chromatography in accordance with other objectives of the present invention; then one or more of the compounds of the formulas [71 ;: or any combination derived from them X or IX > VIII 0 0 a XXX

Ye.

JHO06X10OX; Wm OH

VI VIII IX X

9.46

They can form as by-products in the reactions described above. By-products can be detected and quantified by routine methods, such as Jal C1701 or LCMS. In some examples 0 the present invention includes compositions comprising a compound of formula IV or 1 and at least one by-product of formula VII ¢ 7111 p 1; or X . And in some examples; Xo is di . And in other examples; The by-product of formula VT ; VIL; IX or 76 is found in configurations as a trace element (eg. FL of approximately 790 by weight). And in some examples; The secondary product is present in Al-Takween in a smaller quantity than approximately 7460; less than approximately 7700 ; less than approximately Jc TY of approximately 7100 ; JF nearly 70; less than nearly 77; less than approximately TY less than approximately 70.59 ; less than approximately 70,1; less than approximately; or less than approximately 70.01 by weight divided by the total weight of the composition + in a preferred example 0 when 11076 is methanol; the compound of formula IX is present in an amount less than approximately 70.1; with a lower preference of approximately 70,08; or 0 with greater preference less than approximately 070.0 in a composition containing Formula 1 or ods IV Other examples; when 11076 represents methanol; The product preferably does not contain a compound of formula 176 in the composition containing formula [or 17]. And in some examples; The by-products, squarates of formula VII or IX, which exist in formations containing cyclic bicyclic phosphate ester compounds of formula IV, can be hydrolyzed to form squarate acid of formula X through suitable reaction conditions for the hydrolysis of a phosphate ester of formula TV to form phosphate of formula 1. according to; the present invention includes compositions containing a compound of Formula 1 and a compound of Formula [71 or #2]. In some examples; the amount of a compound of formula VI or 36 in a composition containing formula 1 re is less than approximately 7800 ; al which is approximately 740; less than nearly IT

no more than 7780; less than approximately 700 ; less than nearly 78; less than nearly 77; less than nearly 71; less than approximately 70,5; less than approximately 1 ; less than approximately 70.05; Less than approximately 70.01 by weight divided by total composition. o as used here; The expression "alkyl" or "alkylene" means that it refers to a saturated hydrocarbon group which is straight Alu Lull; branched or rounded. Examples of alkyl groups include methyl « ethyl ; propyl (e.g. “n-propyl” and isopropyl “butyl” (e.g. n-butyl gle ¢ isobutyl ¢ n-butyl secondary butyl tertiary butyl) -butyl \.¢ pentyl 0 Sie) pentyl n-pentyl ; isopentyl » neopentyl (neopentyl and the like. The term "alkylhalo" refers to an alkyl group replaced by one or more than one halogen atom. Example of alkylhalo halogen groups include CHF, and .CF; as used here, the term "alkenyl" refers to an alkyl group It has one or more carbon-carbon double bonds (JL). “butadienyl butadienyl; double carbon-carbon . An example of alkynyl groups includes ethynyl Jd ; propynyl « butynyl ; pentynyl; and similar. as used here; the term halo refers to fluorine, chloro; Yo bromo bromo; 1000 would like. 9.45

Ya

- Refers to a -0-alkyl 'alkoxy' group. As used herein, the expression 'meth' includes a methoxy, an alkoxy form of the alkoxy groups. 0 - alkyl n-propoxy ¢ Se) Propoxy propoxy ¢ ethoxy ethoxy + oxy . ; and similar t-butoxy; Tertiary butoxy (iSOPropoxy; and isopropoxy as used herein; the term "aryl-9H" refers to monocyclic aromatic hydrocarbons, for example "polycyclic aromatic hydrocarbons indanyl" phenanthrenyl anthracenyl ¢ naphthyl phenyl phenyl and the like In some examples, the aryl groups include ¢ indenyl » indanyl

Cus SEAT from as used herein; The term 'reaction' refers to bringing together 1 chemical reactants so that a chemical transformation takes place to form a compound component different from any initial introduction of a chemical into the system as used here. can be selectively displaced by another part; For example by nucleophilic substitution of a chemical. and as an eli during a typical nucleophilic or 0 nucleophilic elimination; The leaving groups include fragments that when separated by nucleophilic or nucleophilic removal, nucleophilic substitution. The leaving groups are well known in the field and include; « bromide bromide ¢ chloride chloride ¢ (Be) halides on halides « Mie » mesylate for example aryl sulfonates and aryl sulfonates - alkyl and alkyl 00 ¢ triflate triflate ¢ nosylate brosylate, tosylate, and the like, and in various places in the present specification. on each independent substratum of elements for all groups and modifiers, eg; YO

The expression “alkyl is composed of 1-1 carbon atom allyl”,©; is specifically intended to discuss methyl; ethyl; an alkyl composed of * alkyl carbon atoms and n; an alkyl of; carbon atoms © ,alkyl; an alkyl of * Cs alkyl carbon atoms; an alkyl is composed of 6 alkyl carbon atoms and L. 8 as current road compounds can contain one or more asymmetric atoms; thus providing optical isomers optical isomers (enantiomers and diastereomers) ¢ Methods of the present invention include all optical isomers (enantiomers 5) and diastereomers (geometric isomers; in addition to racemic 0 and dissolved The enantiomerically pure stereoisomers S sR enantiomerically pure ¢ in addition to other mixtures of stereoisomers 1 and 8 and their derivative salts that are pharmacologically acceptable Optical isomers can be obtained in pure form by means of standard methods known to experts in field; includes; without limitation; on the formation of a diastereomeric salt » kinetic dissolution; 1 and asymmetric preparation. It is further understood that the invention, Jal, includes the domain isomers 95 and mixtures derived therefrom; which can be obtained in pure form by standard methods of separation known to an expert in the field; It includes; unmarked column chromatography; thin layer chromatography; And high-performance liquid chromatography. Ye the methods described here can monitor ly for any appropriate method known in the field. For example; The formation of the product can be monitored by spectral means eg 0 Se nuclear magnetic resonance spectroscopy of the isotope pH 11; or carbon (infrared PCY; spectrophotometer (eg ultraviolet visible); or mass spectrum; or by chromatography.” p.

Ye or HPLC eg high performance liquid chromatography. thin sluggish Subjects to the processes described herein by oll and preferably made of .noble gas or nitrogen cSt will realize the special features according to the present invention; which ° to clarify; described in the course of separate examples; It may also be available in conjunction with a single example. On the contrary ; The various features according to the present invention which are; for short; described in the context of a single example; It may be available separately or in combination. Appropriate The invention will be described in greater detail by way of qualitative examples. The following examples are given for illustrative purposes; It is not intended to limit the present invention in any way. Experts in the field will recognize a variety of non-critical parameters that can be changed or modified. To produce the same results, Example No. 1

N-(3-aminopropyl)aminoethanephosphonic acid diethyl ester via N-alkylation of 1,3- \o diaminopropane

ANEO/MeOH A051

HeN Ne * eo NN TT an” SSN So magnetic ml and equipped with a magnetic stirrer 001 gallons capacity to 1 triple flask followed by (Je ©) methanol and nitrogen inlet 0100860 Methanol was added. equivalents) 0 g ¢ £7 mmol; ¥,¥A) 1,3-diaminopropane (7”-diaminopropane (0 min., then 10°C). and stirred for a period of 0.7- YY). The reaction is exothermic. diethyl (2-bromoethyl)phosphonate is added to diethyl (7-bromoethyl) phosphonate (7 0.176 11012, under DBEP control g). The mixture was stirred throughout the day (7,74 lv ( (DBEP): So g)©) silica gel and then transferred to a +00 mL flask; Silica gel was added

mixture over a rotary evaporator. The sample was carried over a short column (to g of silica gel); and repelled by dichloromethane/methanol (9/1 containing IY 517 of SET chapter) 1,3-diaminopropane and the dialkylated product; Then purified with 1/1 dichloromethane/methanol (dicholoromethane/methanol containing 71 17) to obtain the required product as colorless xene (0.37 g ¢ yield 7711 relative to DBEP; purity -7). HPLC range Example No. N-(3-aminopropyl)aminoethanephosphonic acid diethyl ester via PET 1,3-diaminopropane to diethyl vinylphosphonate J MeOH A 01 With an NN PO — Amy + Sa, correct HN to a 00 mL three-neck flask equipped with a magnetic stirrer and a nitrogen insert nitrogen ¢ methanol (ml) and SEY) aminopropane were added 1" ,¥) 1,3-diaminopropane c; VOY mmol; © equivalents) (exothermic 71 to 7 °C). The reaction mixture was stirred for 10 minutes and then 1 diethyl was added phenylphosphonate (aa©) diethyl vinylphosphonate (DEVP) The mixture was stirred 1 day; transferred to a 50 550 mL flask and the methanol separated The residue was collected over a short column (50 g of silica gel) and purified with 1,000 mL of A dicholoromethane (containing (BN 71 and 0001 mL of dicholoromethane/methanol ZY 1 Y/Y) dicholoromethane/methanol Tl2). By evaporating the solvents the product Requirement 06-0 is obtained as a colorless oil (V0 A) g; Yield <798 relative to DEVP » JAA purity = range (HPLC). Example No. 0 “2-[(8,9)-dioxo-2,6-diaza-bicyclo[5.2.0] [-non-1(7)-en-yl]ethyl}phosphonic acid diethyl ester ‎Y.qt

YY

0 — OFt 0 0 pug + MeOH 0 0 0 yeh 0 Non pug JN p0 mL; Equipped with a magnetic stirrer and inlet Ov into a 60 mL three-stage flask) and heat the content to YO + methanol add methanol ¢ nitrogen (mL) and transfer 00 (g) in 0.04 methanol ( ° C. Dissolve diethyl squarate Solution for a syringe. Similarly; dissolve « -(3-Aminopropyl)-7-Aminoethane Phosphonic Acid ©

N-(3-aminopropyl)-2-aminoethane phosphonic acid diethy! ester is a diethyl ester and is transferred to a syringe. The two solutions were added in harmony by (Jo 01) g) in methanol (47) syringe piston inside preheated methanol for 7 hours. The mixture was stirred all day ethyl acetate at room temperature; most of the methanol was evaporated and ethyl acetate was added For the remainder After cooling in an ice bath, filter the product (0.00) g. Productivity (deo) 0 . (N-(3-aminopropyl)-2-aminoethane phosphonic acid diethyl ester Similar to the previous Jot; the crude product protocol in a reaction actually conducted according to the protocol: has the formula squarate contains; in addition to the titled compound On a square boat 0 |

HO OEt (LC/MS) as a trace component (4,17 71 peak range) via the preceding yo; except where it replaces a protocol and in a reaction actually conducted according to the protocol; the crude product contains, in addition to the entitled compound, ethanol The methanolic solvent with ethanol: contains the formula squarate on the squarate compound yy 0 z 0

EtO OEt (LC/MS as a trace component) 1,1) 7 peak range Via the former; The product protocol is in an actual product interaction and according to the content raw protocol; In addition to the titled compound; on a bicyclic compound having -: of the formula ° 0 0

HJH

(LC/MS peak range via IVE) as a minor component; ab) Example 2-[(8,9)-dioxo-,2,6-dicyclo[S.2.0]-non- 1(7)-en-yl phosphonic acid

Hydrolysis of 2-[(8,9)-dioxo-,2,6-dicyclo[5.2.0]-non-1(7)-en- sl ala Ye 2-[(8,9)-dioxo-,2 ,6-diaza- From article No.? yl}phosphonic acid diethyl ester is produced by a reaction with dicyclo[5.2.0]-non-1(7)-en-yl} phosphonic acid diethyl ester and according to the method discussed in the example bromotrimethyethylsilane bromotrimethylsilane From US Patent No. 01,768,157; Or by reacting with chlorotrimethylsilane A No. and according to the method of tetrahydron chlorotrimethylsilane/Nal/methanol/silane [Sodium iodide VO Lama (YA ¢ YAVA). Tetrahedron Lett Lett, as will be realized by the expert in field; many changes and modifications can be made to the proposed examples according to the current invention and without deviating from the true essence

Y¢ It will be said that each of these variations falls within the intent of 0 of the present invention. The present invention means that each of those patents; Printed applications and publications, including cupcakes. Mentioned in the patent document shall be completely merged with the attribution

Claims (1)

Yo Claims_: by process containing pana product -11 \ : 1] ; in a solvent; A compound of the formula dela (Ty 0 p Hon SN 1 SN b y H OR; 11 or Cre alkyl carbon atom 1-1 and each separately is an alkyl of Ry Whereas; f : 0 separately is Q where v atom 1-1 is made of JST gla; Crp alkyl carbon atom 1-1 is an alkyl of A ; and aryl from or aryl haloalkyl carbon q mentioned has the formula ©1103; cuddly . — OR 1 J OR, Yat v 1 and VY : 1 b) hydrolysis of said compound of formula 17 to provide a compound of formula 14 0 0 I z z 1 \_J OH L comprising at least one compound selected from the 1 of claim no. ay gud -7 1 : X 3 IX 6 71116 VII Formulas Y 0 0 0 0 J HO 01 X40 OX; HO OH 1711 vi IX X : IV A composition containing a compound according to the formula -Y 1 0 | i HN N TN S 7 J OR; Iv or Cre alkyl carbon atom 1-1 apart represented by an alkyl composed of Rp s Ry where + yen haloalkyl carbon atom 1-1 haloalkyl composed of ¢ 0.6 Xv ¢ X 5 1606 VII ¢ VII Least one compound selected from groups Jes oo 0 0 — 1 J HO 0: X40 OX; HO OH VII VII IX X A haloalkyl composed of “Cr alkyl carbon atom 1-1” is an alkyl composed of Xo where -” aryl of or aryl haloalkyl carbon atom 1-3 A ethyl of composition according to Claim 7; Whereas, .36 is ethyl + 1 ethyl is Rp ethyl and Rif of composition according to Claim 7; where =o : 1 for the formula Gy is a compound containing 1 - 01 0 0 I. mlb º J OH I : 16 o l « VII ¢ VI and at least one compound selected from the formulas - + 0 0 0 oO 0 5 ¢ HN NH J HO 0 X10 0X, HO OH i VII VIII IX X YA; A haloalkyl composed of Crs alkyl carbon 553 1-1 hm where 7 is an alkyl composed of .aryl or aryl 0 haloalkyl carbon atom 1-1 "