TW200401779A - New aminopropylphosphinic acids - Google Patents

Abstract

Novel compounds of formula I, with the exception of (i) the racemate of (3-amino-2-hydroxypropyl) phosphinic acid; and (ii) (2R/S,3R)-(3-amino-2-hydroxybutyl) phosphinic acid, having affinity to one or more GABAB receptors, their pharmaceutically acceptable salts, solvates and stereoisomers, as well as processes for their preparation, pharmaceutical compositions containing said therapeutically active compounds and the use of said active compounds in therapy.

Description

200401779 (ii) Description of the invention: The technical field to which the invention belongs The present invention relates to novel compounds having affinities with one or more GABAb receptors and their qualified salts, solvates and stereoisomers. The present invention also relates to a preparation method thereof, a pharmaceutical composition containing the therapeutically active compound, and a therapeutic use of the active compound. Prior art reflux Gastro-oesophageal reflux disease (GRD) is the most prevalent upper gastrointestinal disease. Current treatment aims to reduce gastric acid secretion or to reduce esophageal acid exposure by enhancing esophageal clearance, reducing esophageal sphincter tension, and gastric emptying. The main mechanism behind reflux is early consideration of the low esophageal sphincter that requires low tension. However, recent studies (such as Holloway & Dent (1990) Gastroenterol · Clin · N · Amer · 19,5 17-535) have shown that most incidental reflux events occur in transient lower esophageal relaxation, hereinafter referred to as TLOSR (transient lower oesophageal sphincter relaxations), that is, relaxations not caused by funerals. It has also been shown that gastric acid secretion is generally normal in patients with GORD. Therefore, compounds are needed to reduce the incidence of TLOSR and prevent reflux. A pharmaceutical composition containing a local anesthetic in combination with inhibited esophageal sphincter is published in WO 87/04077 and US 5,03 6,057. GABAb-receptor agonists have recently been shown to inhibit TLOSR, which was published in WO 98/1 1 885. GABAtt deodorant agonist

O: \ 88 \ 88350DOG 200401779 GABA (4-aminobutyric acid) is an endogenous nerve conductor in the central and peripheral nervous system. GABA receptor conventions are divided into 0.886 and GABAb subtypes. GABAb receptor belongs to the superfamily of G-protein coupled receptors. gaBAb receptor agonists have been shown to treat CNS disorders such as spinal spastic internal muscle relaxants, cardiovascular disorders, asthma, intestinal motility disorders such as allergic bowel syndrome (IBS), and pre-exercise and antitussive agents. . GABAB receptor agonists have also been published to effectively treat vomiting (WO 96/11680) and recently as previously mentioned to inhibit TLOSR (WO 98/11885). The most studied GAB AB receptor agonist is baclofen (4-amino-3- (chlorophenyl) butanoic acid, published in Swiss Patent No. ch 449,046. Baclofen is used as an antispasmodic The agent has been used for several years. EP 0356128 shows that the third compound (3-aminopropyl) methyl phosphinic acid is an effective GaBAb receptor agonist for treatment. EP 0181833 published substituted 3-aminopropyl phosphinic acid. It was found to have a very strong affinity for the GAB AB receptor position. Similar to baclofen, this compound can be used as a muscle relaxant, etc. EP 0399949 published (3-aminopropyl) methyl phosphinic acid is described as effective GAB AB Receptor agonists. These compounds are reportedly suitable for use as muscle relaxants. Both EP 0463969 and FR 2722192 apply for 4-aminobutyric acid derivatives with various heterocyclic substituents on the 3-carbon of the butyl chain. The structure-activity relationship of several phosphinic acid homologs related to their affinity for GABAB receptors and their effect as muscle relaxants is discussed in J. Med. CHem. (L995) 38, 3297-33 12. The conclusion of this article is based on The (S) -enantiomer of methyl phosphinic acid can achieve a considerably stronger muscle relaxation effect without the use of baclofen CNS effects appear. Phosphonic acids are also known in the literature as O: \ 88 \ 88350 DOC -8-200401779 (phosphonons acids). These are two names of the same compound, both of which are available. However I have selected phosphinic acids as the compounds according to the present invention. SUMMARY OF THE INVENTION The present invention provides novel compounds of formula I and their pharmaceutical qualified salts, solvates and stereoisomers: HR,

Inside 3 Rt style inside

Ri stands for hydrogen, several groups, low-carbyl, low-alkoxy, or halogen; R2 stands for hydroxyl, sulfhydryl, halogen, or oxy; Han 3 stands for hydrogen or low-carbon (optionally, several groups, mirror, low-oxyl, and low sulfur) (Alkoxy or aryl substituted); R4 represents argon, lower alkyl (optionally substituted with aryl) or aryl; and its pharmaceutically acceptable salts, solvates and stereoisomers, except the following: i) (3-Amino-2-hydroxypropyl) phosphinic acid racemate, and ii) (2R / S, 3R)-(3-amino-2-hydroxybutyl) phosphinic acid. Within a preferred embodiment

Ri represents hydrogen, lower oxygen or halogen; R2 represents halogen, radical or oxygen; O: \ 88 \ 88350 DOC -9- 200401779 R3 represents hydrogen; and R4 represents hydrogen; except (3-amino-2-hydroxypropyl Except for phosphinic acid, even better compounds are (3-amino-2-fluoropropyl) phosphinic acid, (211) _ (3-amino-2-fluoropropyl) phosphinic acid, ( 2S) _ (3-Aminofluoropropyl) phosphinic acid, (3-Amino-2-fluoro-1-methylpropyl) phosphinic acid, (3-Aminooxypropyl) phosphinic acid, 酸-(3-Amino-2-hydroxypropyl) phosphinic acid, (r) _ (3-Amino_2_hydroxypropyl) phosphinic acid and (3-Amino-1-fluoro_2-wei (Propyl) phosphinic acid. It is necessary to know in the present invention that the bond between carbons is a double bond when ~ is -oxy. In the present invention, it is necessary to know that the so-called " low, " groups and compounds are, for example, a maximum of (including) 7 ', especially a maximum of (including) 4 carbon atoms. Also common terms have the following meanings: n-propyl or n-butyl, and iso-C ^ C7 alkyl such as pentyl, low alkyl, such as alkyl, such as methyl, ethyl, ethyl, ethyl, isobutyl, tertiary or tertiary butyl, but Can also be mono-heptyl or heptyl. Low alkoxy systems, such as c-unit milk suspensions, such as methoxy, U-L, n-propoxy or n-butoxy, and isopropoxy, iso-butoxy, second or third butoxy A CyC7 alkoxy group such as pentyloxy, hexyloxy or heptyloxy.

Low-sulfur alkoxy groups are, for example, Cl_C4 alkoxy, such as thiomethyl ^ H oxygen, n-thiopropoxy or n-thiobutoxy, and thioisopropoxy, thioisobutoxy, thiodithiobutoxide, or third sulfur. Butoxy, but it can also be a c, oxy group such as sulfur: oxy, thiohexyl, or thioheptyloxy. The functins are, for example, quotients with the highest atomic order and including 35, such as fluorine or chlorine. O: \ 88 \ 88350 DOC -10- 200401779 is less bromine. The compound of formula I according to the present invention has an amphoteric nature and may exhibit an intramolecular salt form. It can also form acid addition salts and alkali salts. These salts are especially qualified addition salts of pharmaceuticals and qualified salts of pharmaceuticals formed in accordance with the test. Suitable acids for forming such salts include, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid, or organic acids such as sulfonic acids and carboxylic acids. Base-bearing salts are, for example, alkali metal salts such as sodium or potassium salts, or alkaline earth metal salts such as calcium or magnesium salts, and ammonium salts such as those with ammonia or organic amines. When the molecule has one or more stereocenters, the compound according to formula I can be in a stereoisomeric mixture, i.e. a mixture of diastereoisomers and / or racemates, or in a separate stereoisomer form, ie Individual enantiomers and / or diastereomers. These compounds can also take the form of solvates such as hydrates. The compounds according to formula I can all be used to inhibit TLOSR and thus are useful for treating reflux disorders of the stomach and esophagus. The inhibitory effect of TLOSR also means that the compounds of formula I can be used to treat nausea in infants. Effective treatment of nausea in infants is an important method to control the spread of failure caused by excessive loss of nutrition. Moreover, the novel compounds can be used to treat GORD-related or non-GORD-related asthma, wheezing, coughing, pain, coca addiction, hiccup, IBS, indigestion, vomiting, and nociception. Contrary to previous techniques (J. Med. CHem. (1995) 3297-3312 and The GABA Receptors, 2nd edition, edited by SJ Enna & Norman Bowery, Humana Press (1997) Special 28 p. 1-282), according to Although the compound of the present invention contains a P- 安 bond, it has unexpectedly high metabolic stability. These compounds also have surprisingly high therapeutic indices. O: \ 88 \ 88350 DOC -11-200401779 The compound of formula I according to the present invention can be prepared by one of the following methods a) the compound of formula II

Inner heart with! ^ Same as defined above for Si, χ is hydrogen or a protecting group such as -CCH3 (〇CH2CH3) 2, Z is a protecting group such as a third-butoxycarbonyl group, γ is hydrogen or a fluorenyl group such as a lower alkyl group, this formula II The compound is synthesized by a condensation reaction according to the scheme, which uses an amino ester in which R3 is appropriately N-protected as previously defined, w is a protecting group such as a lower alkyl group, Z is as described in Formula II, and an appropriately protected The center of the phosphinic acid derivative is as described in the formula, X * γ is explained in the same formula as π, and a base such as diisopropylamine,

Flow chart 1 If R4 is not equal to hydrogen, then it will be converted by a N_alkylation reaction to introduce IU ', and then the compound of formula III will be obtained by hydrolysis O: \ 88 \ 88350 DOC -12- 200401779 where Ri, R3 and R4 are as The definition of formula I, if necessary, convert the obtained compound into another compound of formula III, the resulting isomer mixture is separated into individual isomers and / or the salt obtained in this method is converted into the free compound of formula m or into Another salt, and / or if necessary, convert the obtained free compound of formula m into a salt equivalent to the above definition; or the compound of formula II is converted by a reduction reaction, and if L is not hydrogen, then it is optionally subjected to Nk reaction 'and taken Post-hydrolysis reactions to obtain characters

R

Η I Η ONPIO / —, where R ^ R3 and R4 have the same meaning as the above formula, if necessary, the obtained compound is converted into a compound of another formula 1V, and the obtained isomer mixture is separated into individual isomers and / or obtained by this method The salt is converted to a free compound of formula IV or into another salt and / or the free compound of the formula is converted to a salt equivalent to the above definition if necessary; or the compound of formula II is converted by reduction and subsequent deoxyhalogenation If R4 is not equal to hydrogen, you can use 1 alkylation reaction to introduce R4 at will, and finally hydrolyze to obtain compound of formula V ~ O: \ 88 \ 88350 DOC -13- 200401779

Ri, R3, and R4 are the same as described in the formula I above. Halo is a halogen atom. If necessary, the obtained compound is converted into another compound of formula V. The isomer mixture obtained is separated into individual isomers. The compound of formula V is either another salt and / or if desired the free compound of formula V is converted to a salt corresponding to the above definition; or b) a compound of formula VI

In the formula, R !, R3 and R4 have the same meanings as in the above formula I, χ is hydrogen or a protecting group such as -CCH3 (OCH2CH3) 2, T is a group capable of being converted into an -NH2 group, and γ is hydrogen or a protecting group such as a lower alkyl group. This compound of formula VI can be synthesized according to the condensation reaction according to Scheme 2, using a 2,3-epoxypropyl derivative such as a suitable N-protected 2,3-epoxypropylamine derivative or an epichlorohydrin derivative, Among them, 1 ^ and 3 are the same as those described in the above formula I, and the phosphinic acid derivatives activated by 0-silylation are suitably protected, wherein X and Y are as explained in formula VI, and Lewis acids are as anhydrous Znci2, O: \ 88V88350 DOC -14- 200401779

Lewis acid

Scheme 2-The reaction in which the dimethylsilyl group is replaced by a hydrogen atom, in which the T group is converted to it as described in Formula VI! ^ Interpretation is the same as the reaction of _NHr4 in Formula j above, and finally the hydrolysis reaction is transformed into Formula IV Compound u? H 〇ph 11 (lv) where R !, R3 and R4 are as described in the above formula I, if necessary, the obtained compound is converted to the compound of formula II, and the obtained isomer mixture is separated into individual isomers and / Or the salt obtained by this method is converted into a compound of formula IV or another salt, and / or the free compound of formula IV is converted to a salt corresponding to the above definition if necessary; or the compound of formula VI Substitution conversion reaction, oxidation reaction, conversion of the T group as in formula VI to a reaction in which L is the same as -NHR4 described in formula J above, and finally a compound of formula Iπ is obtained from the hydrolysis reaction: O: \ 88 \ 88350 DOC -15- 200401779

Wherein Ri, R3 and R4 are as defined in the foregoing formula I, if necessary, the obtained compound is converted into another compound of formula III, the obtained isomer mixture is separated into individual isomers and / or the salt obtained by this method is converted into formula III-free The compound or another salt 'and / or if necessary, the free compound of formula III converted to a salt equivalent to the above definition; or a conversion reaction of a compound of formula VI via hydrogen to replace its trimethyl fragment, a deoxyhalogenation reaction, The formula is as described in Formula VI, and the reaction of r4 with -NHR4 as defined in the previous formula 1 is converted into a compound of formula V.

In the formula, r3 & r4 has the same meaning as in the previous formula j, Hal0 is a dental atom, and if it is necessary to privately transfer the known compound into another compound of formula V, the isomers obtained are separated, and the individual isomers' and / or this The salt obtained by the method is converted into a free compound of formula V αΓ into 3 salts and / or 'if necessary, the free compound of formula V is converted to a salt equivalent to the aforementioned definition; or a compound of magic formula VII-

O: \ 88 \ 88350 DOC -16- 200401779

In the formula, R! Is the same as that described in the formula I above, x is hydrogen or a protecting group such as CCH3 (〇CH2CH3) 2 'U is an electron withdrawing group such as -CD or _c〇2Et which can be converted into -CH2NH2 group, and Y is hydrogen or A protecting group such as a low alkyl group, Hal0 is a self-atom, and the compound of the formula VII can be synthesized by an addition reaction according to Scheme 3, which uses an unsaturated compound, wherein R1 is the same as the formula ^ described above, 1; Explained in formula VII, a suitably protected phosphinic acid derivative activated with 0-silanization, where X and Y are as described in formula VII,

Scheme 3 The reaction converts the U group to -NHR4, wherein R4 is the same as that described in formula I above, and a compound of formula VIII is obtained by a hydrolysis reaction.

O: \ 88 \ 88350 DOC -17- 200401779 In the formula, 1 and 4 have the same meanings as in the previous formula i, Hal0 is a halogen atom, and if necessary, the obtained compound can be converted into another compound of formula VIII, and the obtained isomer mixture can be separated. Into individual isomers and / or convert the salt obtained by this method into a free compound of formula VIII or into another salt, and / or if necessary, convert the obtained free compound of formula VIII into a salt equivalent to the above definition; or d) Compounds of formula IX can be in the form of individual stereoisomers R4 Halo 〇z 'Ahren H (IX) R3 R1 〇, Si [where R !, such as formula! It is stated that _ a protective group such as the third butoxy group and she is a 'atom' This compound of this formula can be synthesized by a substitution reaction according to Scheme 4 'which uses an electrophilic compound where "a is as described above, L is -Dissociative groups such as moth, 2 and system. The same meaning as before, and phosphinic acid activated by 〇_㈣ reaction,

Scheme 4 O: \ 88 \ 88350 DOC -18- 200401779 which is converted into a compound of formula (V) by a hydrolysis reaction

In the formula, R3 and R4 are as described in the foregoing formula. If necessary, convert the obtained person into another compound of formula (V), and if necessary, separate the obtained isomer = the compound is an individual isomer, and / Or convert the salt obtained by this method into a compound of formula v = compound or another salt and / or convert the obtained free compound of formula v to a salt equivalent to the above definition if necessary; or e) a compound of formula XI

Wherein Ri, R3 and & as explained in the above formula I, X is hydrogen or a protecting group such as -CCH3 (〇CH2CH3) 2, and γ-based hydrogen or a protecting group such as a lower alkyl group. Synthesized via an addition reaction in which unsaturated phosphinic acid derivatives are treated with a thiol (HS) or a proton-soluble compound such as ethiol (in this case, the protecting group is subsequently removed), wherein, & as described in Formula I above,

O: \ 88 \ 88350 DOC -19- 200401779

Scheme 5 It is converted to a compound of formula XΠ by hydrolysis reaction. SH Ο (x ") R3 Rt In the formula, Ri, R3 and R4 are explained in the foregoing formula I. If necessary, the obtained compound is converted into another compound of formula XII, and the obtained isomers are separated. To form individual isomers and / or convert the salt obtained by this method into a free compound of formula XII or into another salt, and / or if necessary convert the resulting free compound of formula XII to a salt equivalent to the above definition. Embodiments The following non-limiting examples are used to explain the present invention in more detail. Example 1 (3-Amino-2-aminopropyl) sulfonium under argon in (THF) Add iMBHrTH to the ice-cold solution of ethyl β2 · aspartoxypropyl) (diethoxymethyl) phosphinate in an ice-bath cold solution. After 0 minutes, the solution was heated under reflux for 2.5 hours. The solution was cooled to room temperature and 6 N HC1 (200 ml) was added. The T3HF was removed by rotary evaporation and the aqueous layer was refluxed for another 2.5 hours. The falling liquid was cooled and laughed. The residue was purified by ion exchange O: \ 88 \ 88350 DOC -20- 200401779 column chromatography (DOWEX 50WX-8-200, H + type, 3.5x4_0 cm). The ion exchange resin was pre-washed with 2: 1 methanol / water (400 ml). The crude product was dissolved in 1.1 methanol / water, packed on a column, and washed with 1: 1 methanol / water (400 ml). The eluent was changed to 3.1 methanol / concentrated ammonium hydroxide. The two liquid fractions were combined (150 ¾ total) and evaporated to give 645 ¾ (34%) of (3-amino-2-fluoropropyl) phosphinic acid as a white solid. Data: melting point 2〇3_2〇7; 5 ^^ 0.35 (60: 404 methanol 'dichloromethane, concentrated ammonium hydroxide); NMR (300 MHz, D2〇) 5 7.11 (d, J = 528 Hz, 1H) , 5.18 (dm, J = 54 Hz, 1H), 3.28-3.45 (m5 2H) 5 1.65-2.23 (m5 2H); 13C NMR (125 MHz, D20 + monooxane) 6 87.8 (d, J = 170 Hz) , 44.3 (dd, J = 12.6, 21.6 Hz), 35.6 (dd, J = 20.2, 86.5 Hz); APIMS: m / z = 142 (M + H +). Example 2 Amino-2-Hydroxypropanoate) (S)-(3-Amino-2-hydroxypropyl) (ι, ι_diethoxyethyl) phosphinic acid ethyl ester (1 · (0 g, 3.5 mmol) and concentrated HC1 (50 ml) were heated under reflux for 2 hours. The solution was cooled to room temperature and evaporated. The residue was dissolved in methanol (100 ml) and treated with propylene oxide (2 ml) at room temperature. After the mixture was stirred for 5 hours, the solvent was decanted and the precipitated solid was collected. The solid was dried under argon to give 220 mg (45%) of (S)-(3-amino-2-hydroxypropyl) phosphinic acid as a white solid. Data: iH NMR (300 MHz, D20) 5 7.1 (d, J = 540 Hz, 1H), 4.2 (m, 1H), 2.9-3.2 (m, 2H), 1.7-2.0 (m, 2H); 31p NMR (121 MHz, D20) 5 24.2 (d, J = 522 Hz); FABMS: m / z = 140 (M + H +); [α] 0 at 0.5% in 0.1M HC1). Example 3 (R)-(3-Amino-2-lightpropyl) phosphinic acid (R)-(3-Amino-2-hydroxypropyl) (1,1-diethoxyethyl) A mixture of ethyl phosphonate O: \ 88 \ 88350 DOC-21-200401779 (0.9 g, 3.2 mmol) and concentrated HC1 (50 ml) was heated under reflux for 2 hours. The solution was cooled to room temperature and evaporated. The residue was dissolved in methanol (50 ml) and treated with propylene oxide: 3 yuan (3 liters) at room temperature. The mixture was stirred for 5 hours, and the solvent was decanted to collect a precipitated solid. The solid was dried over argon to give 260 mg (59%) of (r)-(3-amino-2-hydroxypropyl) phosphinic acid as a white solid. Data, η nmR (300 MHz, D20) 5 7.1 (d, J = 540 Hz, 1H), 4 · 2 (m, 1H), 2.9-3.2 (m, 2H) 5 1.7-2.0 (m5 2H); 31P NMR (121 MHz? D2〇) 5 23.9 (d5 J = 525 Hz); FABMS: m / z = 140 (M + H) +; [a] r ^ 20 ° C = -8. (0.5% within 0.1M HC1). Example 4 (3-Aminoaminopropyl) phosphine_ [3- [N-Third-butoxycarbonyl] amino] _2_oxypropyl] (1, ^ diethoxyethyl) phosphinic acid A sample of ethyl ester (8.11 g '21.0 mmol) was dissolved in 3 n HC1 (400 ml). N2 bubbles were first introduced into the falling liquid to deoxidize. The mixture was stirred at room temperature for 4 hours and then concentrated. The residue was co-evaporated with methanol. The residue was then dissolved in methanol (10 ml) and propylene oxide (10 ml) was added. The mixture was stirred for 6 hours, and the obtained Shen Dian was isolated by filtration. The solid was washed with cold methanol and dried under vacuum at 50 ° C to give 2.1 g (73%) of (3-amino-2-oxopropyl) phosphinic acid as an off-white solid. Data: Melting point: 126-127 ° C; Rf = 0.64 (85:15 methanol: water); NMR (300 MHz, D20) 5 7.13 (d, J = 551 Hz, 1H), 4.14 (s, 2H), 3.14 (d, J = 18 Hz, 2H); 13C NMR (75 MHz, D20 + dioxane) 5 199.5, 49 · 2, 47.3 (d5 J = 69 Hz); FABMS: m / z = l38 (M + H) + 〇 Example (.2 mutual: _)-(3_amine _2-gas propyl, phosphine age in a three-necked 2 liter flask equipped with a mechanical stirrer, thermometer, addition funnel and argon bubbler Add ammonium hypophosphite (73 · 8 g, 0.89 mol). Place the bottle at room temperature O: \ 88 \ 88350 DOC -22- 200401779 'Add N, 0-bis- (trimethylsilyl) acetamidine in a water bath Amine (215 ml, 0.87 Molar-BSA) was kept at a speed of less than 38 ° C (about 30 minutes) by keeping the internal temperature under ice cooling. After the BSA was added, the reaction mixture was heated to 45_48 < ^ and maintained at this temperature. 1 hour. The reaction was cooled to room temperature, and (2R) -2-fluoro-3-iodopropylaminocarboxylic acid tert-butyl ester (27.3 g, 27.3 g) in dichloromethane (300 ml) was added. 009mol) solution in the reaction mixture. The reaction was stirred at room temperature for 8 hours. The reaction mixture was cooled to 0 ° C, cautiously with methanol (275 milliliters). ) The reaction was stopped with water (32 ml). After the reaction mixture was stirred for 30 minutes, it was filtered and washed with methanol. The filtrate was concentrated and the residue was placed under high vacuum (0.1 mm Hg) overnight. Methanol, concentrated ammonium hydroxide solution (80: 20: 1) solution was used to grind the crude residue and filtered. The filtrate was concentrated under reduced pressure and repeatedly milled. The crude concentrate was transferred to a 2 liter flask> Gu Yujiazui (375 Aisheng) was placed in a room temperature water bath. A saturated solution of vaporized hydrogen in ethyl acetate (500 ml) was added and the mixture was stirred for 3 hours. The reaction mixture was filtered and washed with a methanol-ethyl acetate (90:10) mixture. Solid. The filtrate was concentrated under reduced pressure, and the crude product was passed into a 100 \ ¥ 6 \ @ 50 \ ¥ 乂 8-200 mesh 11+ formula (500 g, 8X15 cm) and eluted with 1: 1 methanol / water until TLC. No other substances were detected by analysis. The necessary crude product was subsequently eluted with 1: 3 concentrated ammonium hydroxide solution / methanol. The product was further purified by column chromatography with chloroform, methanol, and concentrated ammonium hydroxide (6: 3: 1) solution Elution gave (2R)-(3-amino-2-fluoropropyl) phosphinic acid (3.12 g, 24%) as a white solid. LR NMR (300 MHz, Ό20) δ 7.90 (s, 0.5 Η), 6.15 (s5 0.5 Η), 5.12-5.29 (m, 0.5 Η), 4.92-5.10 (m, 0.5 Η), 3.12-3.42 (η, 2 Η) ， 1.74-2.26 (m ， 2Η) ° Example 6 (2SVH-Amine-2-Fluoropropyl) Phosphonic acid O: \ 88 \ 88350 DOC -23- 200401779 Equipped with mechanical stirrer, thermometer, addition funnel and argon A three-necked 2-liter flask with a bubbler was charged with ammonium hypophosphite (581 g, 0.70 mol). Addition 0_ Bis (tris (silyl) ethyl) amine (175.9 ml, 0.71 mole-BSA) at a rate that maintains the internal temperature at 35-40X :. After the addition of BSA was complete, the reaction mixture was kept at 35_4 (rc for 45 minutes. Dichloromethane (150 ml) was added, and the mixture was stirred at 35-4 (TC and 45 knives of bismuth). The reaction was cooled to room temperature. A solution of (2S) -2-fluoro-3-oxopropylamino acid third butyl ester (42.5 g, 0.14 mol) in methane (300 liters). The reaction was stirred at room temperature. Overnight. Cool the reaction mixture to carefully stop the reaction with methanol (150 mL) and then with water (60 mL). Concentrate the reaction and place the residue under high vacuum (O mm HG). Add concentrated ammonium hydroxide ( 50 ml) Adjust the residue to about 1) 11 8 After adding dichloromethane (400 ml) and methanol (250 ¾ liters). The solid obtained was filtered off, and the filtrate was concentrated. Dichloromethane, methanol, concentrated ammonium hydroxide (80: 20: 1; 400 ml) The solution was ground and the residue was filtered. The filtrate was concentrated under reduced pressure, and the crude concentrate was dissolved in methanol (400 ml). Hydrogen chloride in ethyl acetate (600 ml) was added. Saturate the solution with gas and stir the mixture for 3 hours. Filter the reaction mixture and concentrate the filtrate under reduced pressure. Pass the crude product into Dowex ® 50WX8-200 mesh H + (450 g) column was eluted with 1: 1 methanol / water until TLC analysis was no longer detected. Then the necessary crude product was eluted with ι ·· 3 concentrated ammonium hydroxide solution / methanol. The product was purified by column chromatography and washed with dichloromethane, methanol, and concentrated ammonium hydroxide (6: 3: 1) to obtain (2SH3-amino-2-fluoropropyl) phosphinic acid as a white solid. (3.46 g, 17%). IHNMR OOO MHZ, D2C05 7.90 (s, 0.5 H), 6.15 (s, 0.5 H), 5.12-5.29 (η, 0.5 mm), 4.92_5.10 (m, 0.5 Η), 3.12-3.42 (m, 2 Η), 1.74-2 〇 Example 7 (3-amino-1-gas via propyl) phosphinic acid O: \ 88 \ 88350 DOC -24- 200401779 will (3 · (N- (Second butoxycarbonyl) amino) -fluoro-propyldiethoxyethyl) phosphinic acid ethyl ester (180 mg, 4.5 mmol) dissolved in methanol ml), with 3 N hydrochloric acid (20 ml, 60.0 mmol, used immediately after spraying with argon). The mixture was stirred at room temperature under argon for 6 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was dissolved in methanol (5 ml); co-evaporated with methanol under reduced pressure to remove the remaining water. The crude product (70 mg) was purified by column chromatography (1 x 10 cm column) and eluted with dichloromethane, methanol, and concentrated ammonium hydroxide (6: 3: 1). The product-containing fractions were concentrated under reduced pressure, co-evaporated with acetonitrile (2 x 10 mL) followed by methanol (1 x 10 mL), and dried under high vacuum (0.1 mmHg) overnight. This step yielded (3-amino-1-fluoro-2-hydroxypropyl) phosphinic acid as a white solid (40 mg, 56%). 0.5H), 4.60-4.20 (m, 2H), 3.42-3 · 08 (ιη, 2H). fExample 8 (3-Amino-2-fluoro-fluorenyl-methylpropyl) phosphine age Under argon, the% amine group 2-fluoromethyl-3- contained in THF (15 ml) Oxypropyl (diethoxymethyl) phosphinic acid ethyl ester (16 g, 5.3 mmol) was added to an ice-bath cooling solution and 1 M BH3_THF (12.3 ml, 12.3 mmol) was heated to reflux for 10 minutes. 3 hours. Cool the solution to room temperature and add 6 n HC1 (100 ml) dropwise. The mixture was refluxed for 3 hours. The solution was cooled, evaporated, co-evaporated with ethanol after evaporation with water. The residue was subjected to ion exchange chromatography (DOWEX ^ 0WX-8-200, H + type, 3 · 5 × 4 · 0 cm) purification. ^ Zibo exchange resin was prewashed with 2 ·· 1 methanol / water. The crude product was dissolved in 1: 1 methanol / water Packed on its column, washed with 1: 1 methanol / water. Replace the eluent with 3: 丨 methanol / concentrated ammonium hydroxide. Combine the appropriate liquid fractions and evaporate to give 150 mg (15%) of oil (3_ ^ base_2_ Mixture of diastereomers of fluoro-1-methylpropyl) phosphinic acid: Oral milk. Data O: \ 88 \ 88350 DOC -25- 200401779 NMR (400 MHZ, D20) (5 6.2-7.8 (m , 1H), 4.8-5.2 (m, 1H), 3.2-3.5 (m, 2H), 1.8-2.2 (m, 1H), 1.0-1.2 (m, 3H); MS: m / z = 15 6 (M + H) + 〇 The following intermediates are used to prepare the compounds of the present invention. Intermediate Example 11 3-"(Dilactylmethyl) (ethoxy) acrylic acid 1-2 -Gapropionate (Intermediate of the compound according to Example 1) Ethyl (diethoxymethyl) phosphinate (26.0 g, 133 mmol) with 1,1,1,3,3,3-hexamethylethiamine (28 ml, 133 mmol) The mixture was heated under reflux under argon for 2 hours. The mixture was cooled to room temperature and fluorinated acrylate (10.5 g, 89.0 mmol) was added. The reagents were heated to 60 ° under argon. c. Three months later, the mixture was cooled to room temperature, diluted with ethyl acetate (300 ml), washed with 1 N HC1 (2 × 150 ml) and saturated sodium chloride (100 ml). The organic layer was dried over MgSCU and filtered 32.0 grams of butter were evaporated. The residue was purified by column chromatography on a wet-filled silica gel column (6X30 cm) and eluted with 97: 3 digas methyl alcohol / methanol. The appropriate fractions were combined and evaporated to give 16 0 g (57%) of ethyl 3-[(diethoxymethyl) (ethoxy) phosphonium] -2-fluoropropanoate as a clear oil. Data " η NMR (300 MHz5 CDC13) (5 5.32 (dm? 1H)? 4.67-4.77 (m 5 1H) 5 4.18-4.32 (m5 2H)? 3.5 8-3.91 (m? 4H) 3 2.30-2.62 (m5 2H), 1.20-1.41 (m, 9H) Column I2 3-amine group: 3-oxygen Bingmou Bamboo Diethyl Gas A) Knee _ _ (an intermediate of the compound according to Example 1) in 3-[(diethoxymethyl) (ethoxy) phosphino] -2-fluoropropionic acid ethyl alcohol ( 16.0 mg, 51.1 millimoles) was added to a solution of ethanol (22 mL) with concentrated ammonium hydroxide O: \ 88 \ 88350 DOC -26- 200401779 (14.8 N, 3.5 milliliters, 51.1 millimoles). The solution was stirred for 16 hours and evaporated. The residue was purified by chromatography on a wet packed silica gel column (7 x 37 cm) with 96.5: 3.5 dichloromethane / methanol. The appropriate fractions were combined and evaporated to give 3.43 g (27%) of (3-amino-2-fluoro-3-oxopropyl) (diethoxymethyl) phosphinic acid ethyl ester as a clear oil. Data towel NMR (300 MHz, CDC13) 5 6.43 (s, 1Η), 5.70 (s, 1H), 5.21-5.49 (dm, 1H), 4.7 (dd, 1H), 4.18-4.31 (m, 2H), 3.65 -3.91 (m, 4H), 2.21-2.81 (m, 2H), 1.30-1.40 (m, 3H), 1.20-l_28 (m, 6H). J: Example 13 (H: (3-Chloro-2-hydroxypropyl) (1,1-diethyloxyethane) ethyl phosphinate (Intermediate of the compound according to Example 2) (Diethoxyethyl ) Ethyl phosphinate (15.0 g, 71 mmol) was evaporated to dryness with toluene and the residue was mixed with 1,1,1,3,3,3-hexamethylethylsilamine (13.2 g, 82 mmol) Mol) under reflux for 3 hours under argon. The mixture was cooled to room temperature and evaporated. Add (R) -epihydrin (6.6 g, 71 mmol) and anhydrous zinc chloride (2.5 g, 18 hamol) and heat the reagent to 60 ° C under argon overnight. The mixture was cooled to room temperature and diluted with dichloromethane and water. The organic layer was washed with water, dried over MgSO4, filtered, and evaporated to give 20.7 g of butter. Dissolve the residue in 1% acetic acid in methanol (150¾ liters) and stir the solution overnight. The solvent was removed to obtain 17.7 g (82%) of a transparent oil (feet)-(3-Gas-2-hydroxypropyl ^, ^ diethoxyethyl) phosphinic acid ethyl ester. Data—HNMRQOO MHz, CDC13) 5 4.3-4.4 (m, 1H), 4.1-4.3 (m, 2H), 3.5 · 3.8 (ιη, 4H), 1.9.2.4 (m, 2H), 1.5 (dd, J = 2.3, 11 · 4 Ηζ, 3Η), 1.32-1 · 37 (ιη, 3Η), 1.18 丄 24 (111, 6Η). Ethyl) acetic acid (According to the real name of the soil) O: \ 88 \ 88350 DOC -27- 200401779 # 1 in 9% ammonia ethanol (RM3n via propyl) (1,1- Diethoxyethyl) phosphinate (5.0 g, 17 units of osmium + ore ... Mao Mor), the mixture was stirred in an autoclave at room temperature for 4 days, and stirred at 6 (TC for another day. Fu Hair dredging, chrome cutting; ^ / shoes residue in wet-filled silicone tubing column

Purification by the upper chromatography was performed by extracting it with 5% triethylamine in chloroform called 8% Me0. Combine the appropriate liquids to evaporate, add dichloromethane and dilute with water. Add a few milliliters of 10% Na2CO3 aqueous solution to adjust the pH of the aqueous layer and repeat extraction with dichloromethane. The combined organic layer was dried over Na2S04_h to give 0.22 g (26%) of clear oil (CDamino-2-hydroxypropyl) (U-diethoxyethyl phosphinic acid ethyl ester). Data: iH NMR (300 MHz, CDCl3) (5 4.40-4.55 (b, 1H), 4.10-4.30 (m, 2H), 3.55-3.80 (m, 4H), 3.20-3.30 (m, 1H), 3.00- 3.! 〇 („,, 1H), 2.00-2.40 (m, 2H), 1.45-1.53 (dd, J = 3.45 H.7 Hz, 3H)! 1.30-1.40 (m, 3H), 1.15-1.25 ( m, 6H). Should be listed in column 15 (S)-(l-chloro-2- # propyl certain diethoxy Λ-chenphosphonic acid ethyl alcohol (intermediate according to the compound of Example 3) (diethoxyethyl) phosphine After the mixture of ethyl acetate (15.0 g, 71 mmol) and toluene was evaporated to dryness, the residue was mixed with 1,1,1,3,3,3-hexamethylethylsilazane (132 g '82 mmol) Ear) heated to reflux for 3 hours under argon. Cool the mixture to room temperature and evaporate. Add (S) -epichlorohydrin (6.6 g, 71 mmol) and anhydrous zinc chloride (2.5 g, 18 mmol) The reagent was heated to 60 ° C under argon overnight. The mixture was cooled to room temperature, diluted with dichloromethane and diluted with water. The organic layer was washed with water, dried over milli-GS04, and evaporated after filtration to obtain 20.7 g. Yellow oil. Dissolve the residue in 1% acetic acid in methanol (150 ml) and stir the solution overnight. Remove the solvent to obtain 16.8 g (79%) of (S) _ (3-chloro-2-hydroxypropane) as a clear oil. Glycol Ethyl ethyl phosphinate. Data " H NMR (500 MHz, CDCl3) 54.4 (m, O: \ 88 \ 88350 DOC -28- 200401779 1H), 4.2-4.3 (m, 2H), 3.6-3.8 ( m, 4H), 1.9-2.4 (m, 2H), 1.5 (dd, > 2.3, 11.4 Hz, 3H), 1.32-1.37 (m, 3H), 1.18-124 (% 6H). Futu j 16 ( RV (3-Goodyl-2- and propyl) (1,1-diethylethyl) phosphinic acid ethyl alcohol (the intermediate of JI compound according to Example 3) will be dissolved in 9% ammonia in ethanol solution (S)-(3-Chloro-2-hydroxypropyl) (丨, ^ diethoxyethyl) phosphinate (5.0 g, 17 mmol) was taught in an autoclave at room temperature for 6 days, Stir for an additional day at 5 5 C. The solution was evaporated and the residue was purified by chromatography on a wet packed silica gel column with 5% triethylamine in dichloromethane / methanol (5-8% MeOH). Elution. Combine the appropriate fractions, evaporate and dilute with methane and water. Add a few milliliters of 10% NaCO3 aqueous solution to the water layer to adjust the pH and repeat extraction with methane. The combined organic layers are dried over Na2S04 and evaporated 0.9 g (19%) of ethyl phosphinate (RH3-amino-2-hydroxypropyldiethoxyethyl) was obtained as a clear oil. Data NMR (500 MHz, cDCl3) (? 4.1-4.3 (m, 2H), 4.05 (b, 1H), 3.60-3.80 (m, 4H), 2.4-2.9 (m, 2H), 1.7-2. l (m, 2H), 1.4-1.5 (dd, 3H), 1.3-1.4 (m, 3H), 1.2 (m, 6H). Amino i-2-propane-mi-digas) phosphinic acid a chelate (Intermediate of the compound of iLi Kang Example 4 at -i0 ° C in THF (5 ml) in diisopropylamine (30 ml, 21 mmol) solution was added dropwise Normal BuLi (2.5 M in hexane, 8.6 gross liters 21 pen moles). After οο minutes, the reaction was cooled to _78 ° C, and 1 liter of diethoxylate in THF (5 ml) was added dropwise. Ethyl methyl) phosphinic acid ethyl acetate (4.80 g '2. 0 pen moles) solution. After the addition, the solution was stirred at -78 ° C for 1 hour. Dropwise

O: \ 88 \ 88350 DOC -29- 200401779 Add a solution of methyl n-Boc-glycinate (810 mg, 4.3 * mol) in THF (15 ml). After the addition was complete, the reaction mixture was stirred for 45 minutes. Add acetic acid (1.2 pen liters' 21 mol) and warm the reaction mixture to room temperature. The reaction mixture was partitioned between dichloromethane and water, and the two layers were separated. The aqueous layer was extracted once with dichloromethane. The combined extracts were dried over MgSO4, filtered, and evaporated to give 4.89 g of oil. The residue was chromatographed on silica gel and purified by washing with ethyl acetate. The appropriate fractions were collected to obtain 1.2 g (74%) of ethyl (3-amino-2-oxopropyl) (1 ,; μdiethoxy) phosphinic acid as an oil. Data: H NMR (300 MHz, CDC13) 5 5.48 (s, 1H), 4.1 (M.30 (m, 2H), 417 (d, 2H), 3.603 80 (m, 4H), 3.01-3.30 (m, 2H), 1.52 (d, 3H), 1.43 (s, 9H), 1.32 (t, 3H), 1.19 (t, 6H). Example I8 (2R) _3_df based amine V2_ 螽Alcohol The intermediate of the compound according to Example 5) Lithium borohydride (5.3 g, 0.24 mol) was suspended in THF (200 ml) under nitrogen and cooled to -15 ° C with stirring. Suspend (2R) -3- (dibenzylamino) -2-fluoropropanoic acid methyl ester (56.6 g, 0-19 mol) in THF (250 ml), and add the mixture dropwise over} hours; during the addition Keep it below -10. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred at this temperature for 17 hours. The reaction mixture was cooled to 0 C and the reaction was carefully quenched with a saturated aqueous solution of vaporized ammonium (300 mL). Extract with ethyl acetate (2 × 200 ml) and concentrate the organic phase under reduced pressure. The crude residue was dissolved in 2N hydrochloric acid (200 ml, pH about 2), and the aqueous phase was washed with ether (2 x 200 ml). The aqueous phase was basified with 80% ammonium hydroxide in brine (pH approx. 10), extracted with ethyl acetate (3 X 200 ml), dried over anhydrous sodium sulfate (10 g), filtered and decompressed: (2r) _3_ (Dimethylamine O: \ 88 \ 88350 DOC-30-200401779 based) -2-fluoro-1-propanol (48 g, 93%) as a yellow oil. 4 NMR (300 MHz, CDC13) (5 7.15-7.38 (m5 1〇Η) 5 4.65-4.78 (m5 〇5H) 5 4.48-4.58 (m? 〇 · 5Η), 3.50-3.82 (m, 6H), 2_70-2.88 (m, 2H). Multiple examples 19 (2R) ceramide-2-1; drool alcohol is also the intermediate of the compound according to Example 5, and decomposes (2R) -3-diamidinoamino group) _2 _Fluoro-1-propanol (29.2 g, 0. 11 mol) in ethanol (300 ml). Add 10% by weight of palladium hydroxide (π) carbon (50 g), place the mixture on a Parr, shaker, and shake under hydrogen (55 psi) for 6 hours. Observation revealed that the mixture was filtered through a pad of Celite ^ pok when the hydrogen uptake was not repeated. A batch of fresh palladium hydroxide (Made 1) (5 g) was added to the ethanol mixture, and the mixture was further subjected to the above-mentioned hydrogenation reaction conditions for 7 hours. The crude reaction mixture was filtered through Celite®, and concentrated under reduced pressure to give (2R) _3_amino_2_fluoro-propanol, which was mainly in the form of light-colored oil (9.6 g, 96%). iji NMR (300 MHz, CD3OD) < 5 4.78-5.00 (br s? 3H)? 4.49-4.62 (m? 0.5H)? (32-4.46 (m5 0.5H), 3.54-3.70 (m, 2H), 2.70-2.96 (m, 2H). HMX10 (2R) _2-fluoro_3- and propyl group intermediate of a third butyl formate example 5 compound, / glutamin (2R) -3-amino-2 -Fluoro-1-propanol (4.6 g, 49 mmol) in 25% aqueous dioxane (160 ml), potassium carbonate (71 g, 51 mmol) was added and the mixture was cooled to 0 ° C. Di-tert-butyl dicarbonate (η · 6 g, 53 mmol) was added in two portions. The mixture was allowed to warm to room temperature overnight. The crude reaction mixture was concentrated to dryness, water (150 ml) was added followed by potassium hydrogen sulfate. Saturated aqueous solution (until pH = 3). The organics were extracted with dichloromethane (2 × 150 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a colorless oil (2R) -2_

O: \ 88 \ 88350 D〇C -31-200401779 fluoro-3-hydroxypropylcarbamic acid third butyl ester (9.5 g, 100o / o ^ HNMRPOO MHz, CDC13) 5 4.82_5.04 (br s , 1H), 4.62-4.72 (m, 0.5H), 4.48-4.58 (m, 0.5H), 3.62-3.72 (m, 2H), 3.32-3.62 (m, 2H), 3.20- 3.44 (br s, 1H ), 1.48 (s, 9H) ° f Example 111 (2RV2 • 3--3-iodopropylcarbamic acid third butyl ester (intermediate of the compound according to Example 5) Imidazole (26.6 g, 0.39 mol) at room temperature Dissolved in dichloromethane (400 ml). Add iodine (102.5 g, 0.39 moles), stir the reaction mixture at room temperature for 10 minutes, then cool to 0. (:. Add triphenylphosphine (102.5) in 10 minutes G, 0.39 mol) to keep the internal temperature below 10 ° C. (2R) -2-fluoro-3-hydroxypropylaminocarbamate tert-butyl ester in dichloromethane (100 ml) was added dropwise. (60.4 g, 0.31 mole) solution. After completely adding (2R) -2-fluoro-3-hydroxypropylcarbamate, dichloromethane (200 ml) was added. The reaction mixture was warmed to room temperature. Stirring was continued for 17 hours. The reaction mixture was filtered through a pad of Celite (50 g) with additional dichloromethane. Wash with alkane, concentrate the filtrate under reduced pressure, and purify by silica gel column chromatography with digas methane. This process produced (2R) _2-gas-3-dehydropropyl group as a white solid (64.7 g, 68%). The purpose of carbamic acid is 3 g. LR NMR (300 MHz, CDC13) 5 4.80-5.10 (br s, 1H) 3 4.58-4.72 (m, 0.5H), 4.42-4.56 (m, 0.5H), 3.48-3.70 (m, 1H) 3 3.20- 3.46 (m, 3H) ,; L48 (s, 9H).

Uill? (2S) -3-(^ j ^! V2_methyl propionate) According to the intermediate of the compound of Example 6, the (2R) -2- (dibenzylamino) _3_hydroxypropyl acid methyl ester Ester (231.7 g, 0.77 mole) in THF (850 ml), slowly dropwise in THF (400 ml)

O: \ 88 \ 88350 DOC -32- 200401779 DAST (196 g, 1.2 mol) solution. After the addition was complete, the reaction was stirred for an additional 1.5 hours. TLC analysis indicates raw material consumption. The reaction was then cooled to 0 ° C, water (1.5 liters) was slowly added to stop the reaction, and then solid sodium bicarbonate was added to neutralize. After neutralization, a 1: 1 mixture of concentrated ammonium hydroxide / saturated sodium chloride solution was added, and the reaction was extracted with ethyl acetate and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography with ethyl acetate and hexane (1: 4) to obtain the desired compound (188.3 g, 62%) as an oil. 4 NMR (300 MHz, CDC13) 5 7.18 · 7.38 (m, 10H), 5.12-5 · 17 (χη, 0.5Η), 4.95-5.00 (m, 0.5H), 3.81-3.87 (m, 2H ), 3.69 (s, 3H), 3.49-3.55 (m, 2H), 2.90-3.12 (m, 2H). Example 113 (2S) -3- (Diamidamine and alcohol (the intermediate of the compound according to Example 6, lithium borohydride (17.7 g, 0.81 mol) was suspended under nitrogen) in THF (400 ml) while stirring Cool to -15 ° C. Suspend (2S) _3- (difamino) -2-fluoropropionic acid methyl ester (188.3 g, 0.62 moles) in THF (400 ml) and add the mixture dropwise. Add all After the reaction, the reaction mixture was returned to room temperature and stirred at this temperature for 3 hours. TLC analysis indicated that the starting material was completely used up. The reaction mixture was cooled to 0 ° C, and the reaction was stopped with a saturated ammonium chloride solution (300 ml) carefully. After adding 400 ml of water a second time, the reaction mixture was extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude residue was dissolved in 2 N hydrochloric acid, and the aqueous phase was washed twice with water. The water was made with 80% ammonium hydroxide brine Phase was alkalized (pH about 10), extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a buttery (2S) -3- (dibenzylamino) _2_fluoro-1-propane Alcohol (156.6 g, 92%). 4 NMR (300 MHz, CDC13) 5 7.1 5-7.38 (m, 10H)? 4.65-4.78 (m, 0.5H), 4.48-4.58 (m, 0.5H), 3.50- 3.82 (m, 6H), 2.70-2 .88 (m, O: \ 88 \ 88350 DOC -33- 200401779 2H) 〇 Compound gold-amine group: ^ fluoro_ 丨 _propanol Example 6) 1 intermediate of compound) (2S) -3- (Dibenzylamine patchouli-fluoropropanol (391 g, 0.014 mol) was dissolved in ethanol (300 ml). 10% by weight of palladium hydroxide (11) carbon (50 g) was added and the mixture was allowed to stand. Shake overnight on a Parr shaker under hydrogen (55 psi). When the hydrogen uptake is not observed, the mixture is filtered through a Celite pad. Add a batch of fresh palladium hydroxide (11) (5 g ) In the ethanol mixture, and then hydrogenated according to the above conditions, re-fragrant, and when the hydrogen uptake is not observed, the mixture is filtered through Celite celite. The ethanol mixture is added with a batch of fresh palladium hydroxide (11) ( 5g), and hydrogenated for another 12 hours under the aforementioned conditions. The crude reaction mixture was filtered through Celite diatomaceous earth, and concentrated under reduced pressure to give a light yellow oily (2S) _3_amino_2_fluoro_ 丨 _propyl. Alcohol (13.3 g, 100%). 4 NMR (300 MHz, Cd30d) m50 (br s, 3h), 4.49- 4.62 (m? 0.5H)? 4.32-4.46 (m5 0.5H), 3.54 -3.70 (m5 2H), 2.70-2.96 (m, 2H). '1 ~ Fing 115 (2S) _2_Tsai West Tertiary butyl carbamic acid ester (Ljgen intermediate according to Example 6) (2S) -3-Amino-2 · fluoro_1-propanol (38.6 g, 041 mol) was dissolved in 25% Aqueous dioxane (1.4 liters), potassium carbonate (60.1 g, 0.43 mole) was added, followed by di-tert-butyl monocarbonate (99.5 g, 0.46 mole). The mixture was stirred overnight. TLC analysis indicated that the raw material was completely exhausted. Concentrate the crude reaction mixture to dryness, add water (3 liters) to the table, and then add a saturated aqueous solution of hydrogen bisulfate 4 (up to pH = about 3). The organics were extracted twice with dichloromethane, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a light buttery (2S) _2_fluoro_3_hydroxypropylaminocarbamic acid third butyl

O: \ 88 \ 88350 DOC -34-200401779 ester (79.5 g, 99%). 4 NMR (300 MHz, CDC13) δ 4.82-5.04 (br s, 1H), 4.62-4.72 (m, 0.5H), 4.48-4.58 (m, 0.5H), 3.62-3.72 (m, 2H), 3.32- 3.62 (m, 2H), 3.20-3.44 (br s, 1H), 1.48 (s, 9H) 〇1 Example II6 (2S) _2 · fluoro-kispropylaminocarboxylic acid tertiary butyl group according to the compound of Example 6 Intermediate) Imidazole (19.8 g, 0.29 mole) was dissolved in dichloromethane (900 ml) at room temperature, iodine (73.9 g, 0.29 mole) was added, and the reaction mixture was stirred at room temperature for 10 minutes' Then cooled to 0 ° C. Triphenylphosphine (76.3 g, 0.29 mol) was added dropwise over 10 minutes to maintain the interior at a temperature of 1 (TC or lower.) (2S) _2 in dichloromethane (300 liters) was added dropwise. -A solution of tert-butyl fluoro-3-hydroxypropylcarbamate (45.0 g, 0.23 mole). The reaction mixture was allowed to return to room temperature and stirred for an additional 2 hours. The reaction mixture was passed through Celite It was filtered through a pad of Celite and washed with dichloromethane secondly. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography and eluted with dichloromethane. This process produced (2S) -2-fluoroiodopropyl as a colorless oil. Third carbamate (42.5 g, 62 / 〇). H NMR (300 MHz, CDC13) 5 4.80-5.10 (br s5 1H)? 4.58- 4.72 (m? 0.5H)? 4.42-4.56 (ηι5 0.5H), 3.48 3.70 (m, 1H), 3.20-3.46 (m, 3H), 1.48 (s, 9H). Ethyl ethyl hydrazone (igen according to conventional compound 6 nine interstitial substances) in a pressure bottle Suspend sodium hydride (1.4 g, 57.1 mmol) under a nitrogen atmosphere in ™ F (50 gross liters), and cool to agitation while stirring. Add THF (20 units of 4, rb, η) to the mixture dropwise between clocks. , ^ MU Maosheng) in 1 (1, budiethoxyethyl) phosphinic acid ethyl ester Moore) solution , Keep the internal temperature below 0 during the addition

O: \ 88 \ 88350 DOC -35- 200401779 ° C. After the addition was complete, the reaction mixture was stirred at this temperature for 90 minutes. The flask was cooled to -78 ° C, and chlorochloromethane gas (9.7 g, 142.8 mmol) was condensed into the reaction mixture. Remove the septum and seal the bottle with a screw plug. The flask was then returned to room temperature and heated at 50 ° C for 24 hours. Cool the reaction mixture to 0 ° C and carefully stop the reaction with water (25 ml). Dichloromethane (50 ml) was added to the reaction mixture, and the emulsion was filtered through Celite Celite® (20 g). The aqueous phase was extracted with dichloromethane (2 × 100 mL), dried over anhydrous magnesium sulfate, and the organic phase was concentrated under reduced pressure to obtain the crude product (6.93 g) as a pale yellow oil. The crude residue was purified by silica gel column chromatography (6 X 25 cm column) with 20% acetone-hexane. This process produced (42%) (fluoromethyl) (1,1-diethoxyethyl) phosphinic acid ethyl ester as a clear, colorless oil (4.4 g. 1H NMR (300 MHz, CDCl3) 5 4.94-4.54 (m, 2H), 4.32-4.20 (m, 2H), 3.82-3.54 (m, 4H), 1.6 (M.44 (m, 3H), 1.40-1.28 (m, 3H), 1.26-1.08 (m, 6H). Example 118 (3- (N_ (third butoxycarbonyl) amine, vi-fluoro-2, 2-propane, π, 1-shithoxyethyl) sulfenyl_ethyl ester (_ compound according to Example 7 Intermediate) at -10 ° (: in a solution of diisopropylamine (2.5 ml, 14.5 mmol, 3.5 eq) in 1'11? (30 ml) (about 10 minutes) Normal BuLi (14% in hexane, '9.0¾ liter, 14.5 millimoles). After 10 minutes, the reaction was cooled to -78 ° c, and thf (ioml) was added dropwise (fluoromethyl) in 10 minutes. (U • diethoxyethyl) phosphinate (2.0 g, 8.26 mmol, 2 eq). After the addition, the reaction mixture was stirred at -78 ° C for 1 hour. The solution was added dropwise over 10 minutes. A solution of methyl N-Boc-glycinate (0.8 g, 41 mmol) in thF (10 ml) keeps the internal temperature below -70 ° C. The reaction is completed at _78 ° c after complete addition Stir for hours. O: \ 88 \ 88350 DOC -36- 200401779 Stop the reaction with acetic acid (1 ml, 14.5 mmol) and return to room temperature. Add a saturated aqueous sodium chloride solution (75 ml) to the reaction solution. The organic phase was separated. The aqueous phase was extracted with ethyl acetate (2 X 75 φ liters). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a light buttery crude product (2 69 g). The crude product was passed through a column Purification by chromatography (2X35 cm tube column) and elution with 40% ethyl acetate-hexane. This method produces (3- (N-second butoxycarbonyl) amino) _ 丨 _fluoro-2_ oxygen (Propyl) (丨, 丨 diethoxyethyl) phosphinic acid ethyl ester (0.73 g, 44%) which is a clear, colorless oil. ΙΗ NMR (300 MHz5 CDCl3) 5 5.78 «5.24 (m? 2H ) 5 4.52-4.08 (m5 4H)? 3.94-3.50 (m? 4H)? 1.62-1.51 (m? 3H) 5 1.50-1.32 ^ 3H)? 1.42 (s, 9H), 1.30-1.12 (m, 6H) (Dichloromethane νΐ-ϋ'-2-overscore: fc, na-r-ethyl milk ethyl) Ethyl Acetate (intermediate according to the compound of Example 7) in methanol (30 ml) (3_ (N- (Third-butoxycarbonyl) aminofluoro-2-oxopropyl) (ι, ι_diethoxyethyl) A solution of ethyl phosphinate (0.7 g, 18 mmol) in sodium borohydride (76 mg, 20 mmol) was added under a nitrogen atmosphere at -5 ° C. A slight exotherm occurred; however, the internal temperature remained below ·. The reaction mixture was stirred at 0 c for 1 hour. The reaction mixture was quenched with a saturated aqueous sodium bicarbonate solution (5 mL). The crude mixture was concentrated under reduced pressure. The crude residue was extracted with ethyl acetate (30 ml), washed with a saturated sodium chloride aqueous solution (5 ml), and dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure gave a light buttery crude product (580 mg). Two columns were purified by column chromatography, and the performance was consistent with the difference of (3_ (N_third butoxycarbonyl) amino) -1-fluoro-2-hydroxypropyldiethoxyethyl) phosphinate. Enantiomers. The lower polarity appeared to be a diastereoisomeric O: \ 88 \ 88350 DOC • 37- 200401779 structure in a 1 ·· 1 mixture (210 mg, 29%). The 1H NMR analysis of the higher polar fraction was a significant diastereomer (190 mg, 26%). 1H NMR (300 MHz, CDC13) of strong polar compounds (5 5.32-5.04 (br s, 1H), 4.88-4.82 (m, 0.5H), 4 · 72-4 · 68 (m, 0 · 5Η), 4 · 40_4 · 08 (π, 4H), 3.90-3.26 (m, 6H), 1.66-1.52 (m, 3H), 1.5 (M.32 (m, 3H), 1.44 (s, 9H), 1.3 (M .12 (m, 6H). 3-((Diethyl argonium κ ethyl gas group) phosphinofluorenyl 1-fluorobutane λ ester [the intermediate of the compound according to Example 8) (diethoxymethyl Phenyl) phosphinic acid ethyl ester (21.7.0 g, 110 mmol) with 1,1,1,3,3,3-hexamethylethylsilamine (23.3 mL, 110 mmol) in argon Heat to reflux for 2 hours under air. Cool the mixture to room temperature, add difluoroisomeric mixture of ethyl 2-fluorobut-2-ate (14-6 g, 110 mmol). Heat the reagent to 80 ° under argon. C for 1 day and 120 ° C for 2 hours. Cool the mixture to room temperature and add a second portion of trimethylsilyl-activated (diethoxymethyl) phosphinic acid ethyl ester (this is from (diethoxymethyl) Phenyl) phosphinic acid ethyl ester (21.7 g, 110 mmol) and 1,1,1,3,3,3-hexamethylethylsilamine (23.3 ml, 110 mmol) In the same way (Preparation). The mixture was heated to 100 calendar days for 3 days, and then another portion of trimethylstilbene-activated (diethoxymethyl) phosphinic acid ethyl ester was added. The mixture was heated to 100 ° C under argon for 3 days. After cooling to room temperature, it was diluted with ethyl acetate (300 mL). The falling liquid was washed with IN HC1 (2 X 200 mL) and saturated sodium chloride. The organic layer was dried on GSCU, filtered and evaporated to give 42. 〇g of yellow oil. The residue was purified by chromatography on a wet-filled silica gel column, washed with dichloromethane, and then washed with 98: 2 dichloromethane / methanol. The appropriate fractions were combined and evaporated to obtain 3.6 g. %) Clear oily 3-[(diethoxymethyl) (ethoxy) phosphine 醯] _2_fluorobutanoic acid ethyl ester. ΙΗ O: \ 88 \ 88350 DOC -38-200401779 NMR (4GG MHz, CDC13) 5 4.9_5.6 (m, 1Η), 4 · 7- 4 · 8 (ιη, 1H) 4.2-4.4 (m, 4H), 3.6-4.〇 (m, 4H), 2.6-2.9 (m, 1H) ), 1 · 2-1 · 4 (m 12H)., I > jI21 3-Amine-2-fluoro_fluorene-methyl_3_ylpropane (diethylpropane, ethylacetate (compound according to Example 8) Intermediate) Add concentrated ammonium hydroxide (14.8 M, 0.5 ml, 7.4 mmol) to 3-[(diethoxymethyl) in ethanol (3 ml) ) (Ethoxy) acyl phosphino] -2-fluoro-butyric acid ethyl ester (1.8 g, 5.5 mmol) was added. After the solution was stirred at 40 ° C for 24 hours, it was evaporated to give 1.6 g (97%) of 3-amino-2-fluoro-1-methyl-3-oxopropyl (diethoxymethyl) phosphine as a clear oil. Diastereoisomeric mixtures of ethyl acetate. ιΗ NMR (400 MHz, CDCl3) 5 5.7-6.7 (m, 2H), 4.9-5.6 (m, 1H), 4.7-4.8 (m, 1H), 4.1-4.4 (m, 2H), 3.8-4.0 (m 4H), 2.8-3. 0 (m, 1H), 1.2-1.4 (m, 12H). Pharmaceutical Swords Compounds of formula I according to the invention can be used in pharmaceutical formulations for oral, rectal, epidural, intravenous, intramuscular, subcutaneous, nasal and infusion administration or any other suitable route of administration Active ingredient. The preferred method of administration is oral or via injection / infusion. A pharmaceutical formulation contains a combination of a compound of the present invention and one or more pharmaceutical qualified components. The finished medicinal form is manufactured by known pharmaceutical manufacturing methods. Usually, the amount of active compound is between 0.1-95% by weight of the preparation. For parenteral preparations, 0.2-20% by weight is preferred, and oral preparations are preferably 1-50% by weight. The solid dosage unit pharmaceutical preparation for oral administration containing the compound of the present invention is O: \ 88 \ 88350 DOC -39- 200401779. The selected compound can be mixed with qualified components of solid pharmaceuticals (such as decomposers and lubricants). The mixture is then processed into granules, tablets, capsules or sachets. Rectal dosage units can be formulated as suppositories; gelatin rectal capsules; ready-made micro-enemas; or dry micro-enemas are reconstituted in an appropriate solvent and administered immediately. Liquid preparations for oral administration can be prepared in the form of a syrup or suspension, or in the form of a dry mix, and reconstituted with an appropriate solvent before use. The solution for parenteral administration can be prepared as a solution of a compound of the present invention in a pharmaceutically acceptable solvent, which can be adjusted into ampoules or vials. It can also be made into a dry agent and reconstituted with an appropriate solvent immediately before use. The typical daily dose of the active compound will depend on various factors such as the individual needs of each patient, the route of administration and the condition. Typical dosages may range from 1 microgram to 100 milligrams per kilogram of body weight per day, preferably 10 micrograms to 20 milligrams per kilogram of body weight per day. Biological studies [3H] GABA radioligand binding assay to rat neuronal membranes is basically the entire brain of Sprague Dawley male rats as previously described (Zukin, et al. (1974) Proc. Natl. Acad. USA 71, 4802-4807) preparation. Modified by Olpe et al. [(1990) Eur. J. PHarmacol. 187, 27-38] [3H] GABA competition assay using a 96-well microplate in 200 μl TCI (tricalcium isotetrahydronicotinic acid) buffer (50 mM three (tris (hydroxymethyl) aminomethane), pH 7.4, 2.5 mM CaCl2 and 40 // M isotetrahydronicotinic acid) containing 20 nM [3H] GABA (specific activity: 3 Tera Becquerel (TBq) / millimolar), measured O: \ 88 \ 88350 DOC -40- 200401779 Trial combination or solvent with 80 micrograms of nerve key membrane protein. After incubating at room temperature for 12-20 minutes, use a 96-well micro-disc cell harvester (Skatron or Tomtec) to quickly filter through glass fiber filter (printed filter pad B filter, Wallac) and stop incubation. Polyethyleneimine treatment. The filter was washed at 4 ° C with 50 mM three (tris (hydroxymethyl) aminomethane) and 2.5 mM CaCl2 in pH 7.4 buffer, and then dried at 55 ° C. MeltiLex B / HS scintillator flakes (Wallac) were melted on a funnel and radioactivity was measured in a Microbeta scintillation counter (Wallac). Results and Discussion It was found that the compounds of the present invention exhibit high affinity and potency for GABAB receptors in the colon and ileum from low IC50 and EC50, respectively. The compounds have also been found to reduce TLOSR when administered orally and intravenously to animal models. Contrary to the claims of 3-aminopropylphosphinic acid derivatives having P-fluorene bonds in the literature, we have found that the compounds of the present invention have high metabolic stability to animal models. Furthermore, (by measuring temperature reduction in rats) no CNS side effects were observed or only at very high doses. Therefore, the difference between therapeutic agents (inhibition of TLOSR in dog mode) and agents that cause (murine mode) side effects is unexpectedly high. O: \ 88 \ 88350 DOC -41-

Claims (1)

200401779 Scope of patent application: 1. A compound according to formula h h2n ⑴ where Ri represents H, Cw alkyl, halogen, (^ or ^^ alkoxy); and R2 represents OH, SH, halogen, or oxy; and pharmaceutically acceptable salts, solvates, and stereoisomers thereof The limiting condition is that when 1 is 1, r2 is not 0H, fluorine and oxy. 2 · The compound according to item 1 of the scope of patent application, wherein R1 represents C 1 _ 4 alkyl or dentin. 3 . The compound according to item 1 of the scope of the patent application, which is (3-aminosmall fluoro-2. Hydroxypropyl) phosphinic acid. 4. The compound according to the scope of application, which is (3 Tian: a : Glycine, _ 』. Methylpropyl) phosphinic acid 5. 6. A pharmaceutical composition that inhibits transient lower esophageal sphincter relaxant, containing a therapeutically acceptable amount according to the patent application of" 4 — Medical composition for diluent, excipient, or inert carrier, etc. to treat the month and esophageal reflux disease, as appropriate, and include the original, acceptable amount based on any of the patents in the patent park i_ 4 —, " 物 'It depends on the situation and the diluent, Fu, "a record, two * days, M-sex carrier, etc. Drug composition. ,, bar containing burn treatment can be accessed, O: \ 88 \ 88350 DOC 200401779 The compound according to any one of the scope of application patents 1-4, which is optionally combined with a diluent, excipient or inert carrier, etc. 8. The pharmaceutical composition according to any one of claims 5-7 in the scope of the patent application, wherein the amount of the compound is a weight ratio of the composition bounded by 0.1-95%. O: \ 88 \ 88350 DOC 200401779 柒. Designated Representative Map: (1) The designated representative map in this case is: (). (2) Brief description of the element representative symbols of this representative map: (none) 捌 If there is a chemical formula in this case, please disclose the chemical formula that can best show the characteristics of the invention: h2n ⑴ O: \ 88 \ 88350 DOC