CN1030761A - Phosphorated 3-hydroxyl-3-first glutaryl CoA-reductase inhibitors, new intermediate and method - Google Patents

Phosphorated 3-hydroxyl-3-first glutaryl CoA-reductase inhibitors, new intermediate and method Download PDF

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CN1030761A
CN1030761A CN88103699A CN88103699A CN1030761A CN 1030761 A CN1030761 A CN 1030761A CN 88103699 A CN88103699 A CN 88103699A CN 88103699 A CN88103699 A CN 88103699A CN 1030761 A CN1030761 A CN 1030761A
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hydroxybutyric acid
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acid
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唐纳德·史蒂文·卡拉纽斯基
迈克尔·克里斯托弗·巴迪亚
史各特·阿当斯·比勒
艾力克·迈克尔·戈登
迈克尔·约瑟夫·索菲亚
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ER Squibb and Sons LLC
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Abstract

The invention provides can be used as cholesteral biosynthesis inhibitor and thereby can be used as the compound of hypocholesterolemic agents, these compounds have following structure: Wherein R is OH or its salt or lower alkoxy; R XBe H or alkyl; X is-CH 2-,-CH 2-CH 2-,-CH=CH-,-C ≡ C-,-CH 2CH 2CH 2-or-CH 2O-(wherein O links to each other with Z); Z is a hydrophobic conjugated group.The present invention also be provided for preparing above-claimed cpd new intermediate, contain the medicinal compositions of this compounds and suppress the biosynthetic method of cholesterol with this compounds.

Description

Phosphorated 3-hydroxyl-3-first glutaryl CoA-reductase inhibitors, new intermediate and method
The present invention relates to new P contained compound, this compound suppresses 3-hydroxy-3-methylglutaric acid list acyl coenzyme A reductase activity, thereby can be used to suppress the biosynthesizing of cholesterol; The present invention relates to contain the hypercholesterolemia composition of this compounds; Relate to the new intermediate that forms in the preparation process of this compounds; The using method that relates to this compounds that is used for this purpose.
People such as F.M.Singer (Proc.Soc.Exper.Biol.Med., 102,370(1959)) and F.H.Hulcher (Arch.Biochem.Biophys., 146,422(1971)) biosynthesizing that some Mevalonic acid derivative can suppress cholesterol is disclosed.
People such as Endo No. 322 and 3,983, in No. 140 United States Patent (USP)s, disclose a kind of biosynthetic active tunning of the cholesterol of inhibition that has at 4,049, No. 495,4,137.This product is called compression plain (compactin), according to reports people such as (, J.Chem.Soc.Perkin is I.1165(1976) Brown), it has complicated mevalonolactone structure.
English Patent 1,586,152 disclose one group of synthetic compound with following formula:
Wherein, E represents a direct key, a C 1-3Alkylidene bridge or a vinylene bridge, various R represent various substituting groups.
The activity of the compound that this English Patent is reported is lower than compression plain active 1%.
Grant people such as Willard 4,375, No. 475 U.S. Patent Publications have the hypercholesterolemia and a reducing blood-fat compound of following structure:
Wherein A is H or methyl; E be a direct key ,-CH 2-,-CH 2-CH 2-,-CH 2-CH 2-CH 2-or-CH=CH-; R 1, R 2And R 3Be selected from H, halogen, C respectively 1-4Alkyl, C 1-4Haloalkyl, phenyl, by halogen, C 1-4Alkoxyl group, C 2-8Alkanoyloxy, C 1-4Alkyl or C 1-4Phenyl and OR that haloalkyl replaces 4, R wherein 4Be H, C 2-8Alkanoyl, benzoyl, phenyl, halogenophenyl, phenyl C 1-3Alkyl, C 1-9Alkyl, cinnamyl, C 1-4Haloalkyl, allyl group, cycloalkyl-C 1-3-alkyl, adamantyl-C 1-3-alkyl or the phenyl C that replaces 1-3-alkyl, substituting group wherein all is selected from halogen, C 1-4Alkoxyl group, C 1-4Alkyl or C 1-4Haloalkyl; This patent also discloses by hydrolysis and has opened lactonic ring and the corresponding dihydroxylated acid that generates, the acceptable salt of this sour medicine, and the C of this dihydroxylated acid 1-3Alkyl ester, the C that phenyl, dimethylamino or kharophen replace 1-3-alkyl ester; This patent also discloses all that and had the enantiomeric compounds of 4R configuration in the tetrahydrofuran (THF) part of the trans racemoid shown in the following formula.
The WO 84/02131(PCT/EP83/00308 that submits to the name of Sandoz AG) (application number of submitting to according to November 22 nineteen eighty-two is 443,668 U.S. Patent application, the application number of submitting to November 4 nineteen eighty-three is 548,850 U.S. Patent application), the heterocyclic analogs and the derivative thereof of the mevalonolactone with following structure are disclosed, it can free acid form or physiology on hydrolyzable and the form of acceptable ester or δ lactone or the form of salt exist:
Wherein, one of R and Ro are
Figure 881036994_IMG76
, another is uncle or secondary C 1-6Alkyl, C 3-6Cycloalkyl or phenyl (CH 2) m,
Wherein, R 4Be hydrogen, C 1-4Alkyl, C 1-4Alkoxyl group (except the tert.-butoxy), trifluoromethyl, fluorine, chlorine, phenoxy group or benzyloxy,
R 5Be hydrogen, C 1-3Alkyl, C 1-3Alkoxyl group, trifluoromethyl, fluorine, chlorine, phenoxy group or benzyloxy,
R 5aBe hydrogen, C 1-2Alkyl, C 1-2Alkoxyl group, fluorine or chlorine,
M is 1,2 or 3,
Condition is to work as R 4During for hydrogen, R 5And R 5aAll be necessary for hydrogen, work as R 5During for hydrogen, R 5aBe necessary for hydrogen, R 4And R 5There is one to be trifluoromethyl, R at the most 4And R 5There is one to be phenoxy group, R at the most 4And R 5There is one to be benzyloxy at the most,
R 2Be hydrogen, C 1-4Alkyl, C 3-6Cycloalkyl, C 1-4Alkoxyl group (except the tert.-butoxy), trifluoromethyl, fluorine, chlorine, phenoxy group or benzyloxy,
R 3Be hydrogen, C 1-3Alkyl, C 1-3Alkoxyl group, trifluoromethyl, fluorine, chlorine, phenoxy group or benzyloxy, condition are to work as R 2During for hydrogen, R 3Must be hydrogen, R 2And R 3There is one to be trifluoromethyl, R at the most 2And R 3There is one to be phenoxy group at the most, R 2And R 3There is one to be benzyloxy at the most.
X is-(CH 2) n-or-CH=CH-(n=0,1,2 or 3),
Z is II
Wherein, R 6Be hydrogen or C 1-3Alkyl.
GB2162-179-A discloses the naphthyl analogue of mevalonolactone, and this analogue can be used as cholesteral biosynthesis inhibitor, and has following structure:
Figure 881036994_IMG78
R wherein 1=1-3C alkyl;
Z is that structural formula is Z 1Or Z 2Group:
R 7=H, a hydrolyzable ester group or a positively charged ion.
The 164-698-A European patent discloses some and can be used as the preparation method of the lactone of anti-blood cholesterol growth promoter, that is, and and with a kind of organic sulfonic acid halide R 5SO 2X handles a kind of acid amides, removes blocking group Pr then:
X=halogen wherein;
A methyl alcohol of Pr=(hydroxyl) blocking group;
R 1=H or CH 3;
R 3, R 4=H, 1-3C alkyl or phenyl-(1-3C alkyl), this phenyl also can be replaced by 1-3C alkyl, 1-3C alkoxy or halogen;
R 2=one formula (A) or group (B):
Figure 881036994_IMG81
R 6=H or OH;
R=H or CH 3;
A, b, c, d also can be two keys;
R 7=phenyl or benzyloxy, phenyl ring also can be replaced by 1-3C alkyl or halogen under two kinds of situations;
R 8, R 9=1-3C alkyl or halogen;
R 5=1-3C alkyl, phenyl or one or two (1-3C alkyl) phenyl.
Anderson, Paul Leroy, Ger.Offen.DE3,525,256 disclose the naphthyl analogue of mevalonolactone, and its structure is as follows:
Figure 881036994_IMG82
R wherein 1Be alkyl, Z=Q, Q 1; R 7=H, or a hydrolyzable ester group, this analogue can be used as cholesteral biosynthesis inhibitor and can be used for treating atherosclerosis.
The WO 8402-903(that submits to the name of Sandoz AG submitted to according to January 24 nineteen eighty-three, application number is 460,600 U.S. Patent application) disclose can be used as the reducing blood fat protein agent mevalonolactone like thing, it has following structure:
Figure 881036994_IMG83
Wherein two Ro groups common form one as shown in the formula free radical:
R wherein 2Be hydrogen, C 1-4Alkyl, C 1-4Alkoxyl group (except the tert.-butoxy), trifluoromethyl, fluorine, chlorine, phenoxy group or benzyloxy,
R 3Be hydrogen, C 1-3Alkyl, C 1-3Alkoxyl group, trifluoromethyl, fluorine, chlorine, phenoxy group or benzyloxy, condition are R 2And R 3There is one to be trifluoromethyl at the most, R 2And R 3There is one to be phenoxy group at the most, R 2And R 3There is one to be benzyloxy at the most,
R 1Be hydrogen, C 1-6Alkyl, fluorine, chlorine or benzyloxy,
R 4Be hydrogen, C 1-4Alkyl, C 1-4Alkoxyl group (except the tert.-butoxy), trifluoromethyl, fluorine, chlorine, phenoxy group or benzyloxy,
R 5Be hydrogen, C 1-3Alkyl, C 1-3Alkoxyl group, trifluoromethyl, fluorine, chlorine, phenoxy group or benzyloxy,
R 5aBe hydrogen, C 1-2Alkyl, C 1-2Alkoxyl group, fluorine or chlorine, condition are R 4And R 5There is one to be trifluoromethyl at the most, R 4And R 5There is one to be phenoxy group at the most, R 4And R 5There is one to be benzyloxy at the most,
X is
Wherein, n be 0,1,2 or 3, two q all to be 0 or one be 0 and another is 1,
Z is
Figure 881036994_IMG86
R wherein 6Be hydrogen or C 1-3Alkyl, general supplementary condition be ,-X-Z and by R 4The phenyl that replaces is in the ortho position each other;
This analogue exists with the form of free acid, or exists with the form of hydrolyzable on its physiology and acceptable ester or δ lactone, or exists with the form of salt.
Grant Wareing(and transfer Sandoz) 4,613, No. 610 U.S. Patent Publications a series of 7-pyrazolyls-3 with following structure, 5-dihydro heptan-6-olefin(e) acid HMG-CoA reductase inhibitor:
Wherein,
R 1For not containing the C of unsymmetrical carbon 1-6Alkyl,
R 2And R 5Be respectively hydrogen, C 1-3Alkyl, normal-butyl, isobutyl-, the tertiary butyl, C 1-3Alkoxyl group, n-butoxy, isobutoxy, trifluoromethyl, fluorine, chlorine, phenyl, phenoxy group or benzyloxy,
R 3And R 6Be respectively hydrogen, C 1-3Alkyl, C 1-3Alkoxyl group, trifluoromethyl, fluorine, chlorine, phenoxy group or benzyloxy,
R 4And R 7Be respectively hydrogen, C 1-2Alkyl, C 1-2Alkoxyl group, fluorine or chlorine, supplementary condition are R 2And R 3There is one to be trifluoromethyl at the most, R 2And R 3There is one to be phenoxy group at the most, R 2And R 3There is one to be benzyloxy at the most, R 5And R 6There is one to be trifluoromethyl at the most, R 5And R 6There is one to be phenoxy group, R at the most 5And R 6There is one to be benzyloxy at the most,
X is-(CH 2) m-,-CH=CH-,-CH=CH-CH 2-or-CH 2-CH=CH-, wherein m is 0,1,2 or 3,
Z is
Wherein, R 10Be hydrogen or C 1-3Alkyl, R 11Be hydrogen, R 12Or M, wherein,
R 12Be can accept on the physiology and hydrolyzable ester group,
M is a positively charged ion,
Supplementary condition are: (ⅰ)-and the X-Z group is positioned at 4 or 5 of pyrazoles ring, (ⅱ) R 1Group and-the X-Z group is in the ortho position each other.
WO8607-054A(Sandoz-Erfindungen) disclose the imidazoles analogue of mevalonolactone, these analogues can be used for treating high blood lipoprotein disease and atherosclerosis, and have following formula:
R 1=alkyl, cycloalkyl, adamantyl-1 or R 4, R 5, R 6The phenyl (group A) that replaces;
R 2=alkyl, cycloalkyl, adamantyl-1 or R 7, R 8, R 9The phenyl (group B) that replaces
R 3=H, alkyl, cycloalkyl, adamantyl-1, styryl or R 10, R 11, R 12The phenyl (group C) that replaces;
X=-(CH 2) m-,-CH=CH-,-CH=CH-CH 2-or-CH 2-CH=CH-;
m＝0-3;
Z=-CH(OH)-CH 2-C(R 13) (OH)-CH 2-COOR 14(group a) ,-Q-CH 2-C(R 13) (OH)-CH 2-COOR 14The group of (group c) or a formula (b):
Figure 881036994_IMG90
Q=CO or-C(OR 15) 2-;
R 15=uncle or secondary alkyl; Each R 15Identical;
Perhaps, R 15+ R 15=(CH 2) 2Or (CH 2) 3;
R 13=H or 1-3C alkyl;
R 14=H, R 16Or M;
R 16=ester group;
The M=positively charged ion;
Condition is, have only when X be CH=CH or CH 2-CH=CH and/or work as R 13During=1-3C alkyl, Z just can be a group (c);
R 4, R 7And R 10=1-3C alkyl, normal-butyl, isobutyl-or the tertiary butyl, 1-3C alkoxyl group, n-butoxy or isobutoxy, CF 3, F, Cl, Br, phenyl, phenoxy group or benzyloxy;
R 5, R 8And R 11=H, 1-3C alkyl, 1-3C alkoxyl group, CF 3, F, Cl, Br, COOR 17, N(R 19) 2, phenoxy group or benzyloxy;
R 17=H, R 18Or M;
R 18=1-3C alkyl, normal-butyl, isobutyl-or the tertiary butyl or benzyl;
R 19=alkyl;
R 6, R 9And R 12=H, 1-2C alkyl, 1-2C alkoxyl group, F or Cl; Condition is that in (1) A, B and each group of C, it is CF that a substituting group is arranged respectively at the most 3, in each group of A, B and C, it is phenoxy group that a substituting group is arranged respectively at the most, in each group of A, B and C, it is benzyloxy that a substituting group is arranged respectively at the most;
(2) (Q=C(OR when Z is group c 15) 2), this compound is in free alkali form, and, perhaps (ⅰ) R 14Be R 16, each R 17Be respectively R 18, perhaps (ⅱ) R 14Be M, each R 17Be respectively R 18Or M;
(3) work as R 14And/or at least one R 17During for M, this compound is in free alkali form.
Unless otherwise indicated, all " alkyl " all is 1-6C, and do not contain asymmetric C; " cycloalkyl " has 3-7C.
WO8603-488-A(Sandoz AG) disclose the indenes analogue of mevalonolactone, these analogues can be used as reducing blood fat protein agent and antiatherosclerotic.These analogues exist with the form of free acid, or exist with the form of ester or δ lactone, or exist with the form of salt, and have following formula:
R=H or uncle or secondary 1-6C alkyl;
R 1=uncle or secondary 1-6C alkyl;
Or R+R 1=(CH 2) m or (Z)-CH 2-CH=CH-CH 2;
m＝2-6;
R 0=1-6C alkyl, 3-7C cycloalkyl or R 4, R 5, R 6The phenyl that replaces;
R 2, R 4=H, 1-4C alkyl, 1-4C alkoxyl group (except the tert.-butoxy), CF 3, F, Cl, phenoxy group or benzyloxy;
R 3And R 5=H, 1-3C alkyl, 1-3C alkoxyl group, CF 3, F, Cl, phenoxy group or benzyloxy;
R 6=H, 1-2C alkyl, 1-2C alkoxyl group, F or Cl;
Condition is, on each phenyl ring and indenes ring, and CF 3, phenoxy group or benzyloxy all can only have one;
X=(CH 2) n or-(CH 2) q-CH=CH(CH 2) q-;
n＝1-3;
Two q are 0, or one be 0, and another is 1;
Z=-Q-CH 2-C(R 10) (OH)-CH 2COOH exists or exists with the form of ester or δ lactone or salt with the form of free acid;
Q=CO ,-C(OR 7) 2-or CHOH
Two R 7=identical uncle or secondary 1-6C alkyl, or two R 7Be (CH together 2) 2Or (CH 2) 3;
R 10=H or 1-3C alkyl;
Condition is, have only when X be CH=CH or CH 2-CH=CH and/or R 10During for the 1-3C alkyl, Q can not be CHOH.
Grant people such as Hoefle (Warner Lambert) 4,647, No. 576 U.S. Patent Publications the pyrroles that replaces of new C-and N-, these compounds can be used as lipid-lowering agent and hypocholesterolemic agents, and have following formula:
Figure 881036994_IMG92
X=-CH 2-,-CH 2CH 2-or-CH(CH 3) CH 2-;
R 1=1-or 2-naphthyl; Cyclohexyl; Norbornene; By F, Cl, OH, CF 3, the phenyl that replaces arbitrarily of 1-4C alkyl, 1-4C alkoxyl group or 2-8C alkanoyloxy; 2-, 3-or 4-pyridyl or its N-oxide compound; Or
R 5=1-4C alkyl;
Hal=chlorine, bromine or iodine;
R 2And R 3=H, Cl, Br, CN, CF 3, phenyl, 1-4C alkyl, 2-8C carbalkoxy ,-CH 2OR 6Or-CH 2OCONHR 7;
R 6=H or 1-6C alkanoyl;
R 7=alkyl or the phenyl that replaces arbitrarily by Cl, Br or 1-4C alkyl;
Perhaps R 2And R 3Together=-(CH 2) n-,-CH 2OCH 2-,-CON(R 8) CO-or-CON(R 9) N(R 10) CO-;
N=3 or 4;
R 8=H, 1-6C alkyl, phenyl or benzyl;
R 9And R 10=H, 1-4C alkyl or benzyl;
R 4=1-4C alkyl, cyclopropyl, cyclobutyl or CF 3
European patent application 0 221 025 A 1(Sandoz AG) discloses the heterocyclic analogs and the derivative thereof of mevalonolactone, and these compounds have following formula:
Wherein,
Ra is group-X-Z, and Rb is R 2, Rc is R 3, Rd is R 4, Y is a group , or
Ra is R 1, Rb is group-X-Z, Rc is R 2, Rd is R 3, Y is O, S or group
Figure 881036994_IMG96
;
R 1, R 2, R 3And R 4Be respectively the C that does not contain unsymmetrical carbon 1-4Alkyl, C 3-7Cycloalkyl or a ring
Figure 881036994_IMG97
Perhaps R 3And R 4Can also be hydrogen, perhaps when Y is O or S, R 3Can be
Figure 881036994_IMG98
R wherein 17Be hydrogen or C 1-3Alkyl, R 18And R 19Be respectively hydrogen, C 1-3Alkyl or phenyl; Each R 5Be respectively hydrogen, C 1-3Alkyl, normal-butyl, isobutyl-, the tertiary butyl, C 1-3Alkoxyl group, n-butoxy, isobutoxy, trifluoromethyl, fluorine, chlorine, bromine, phenyl, phenoxy group or benzyloxy; Each R 4Be respectively hydrogen, C 1-3Alkyl, C 1-3Alkoxyl group, trifluoromethyl, fluorine, chlorine, bromine, benzene oxygen or benzyloxy; Each R 7Be respectively hydrogen, C 1-2Alkyl, C 1-2Alkoxyl group, fluorine or chlorine, supplementary condition are that in the A of each existence ring, trifluoromethyl, phenoxy group or benzyloxy all can only have one.X is (CH 2) m or
(CH 2) qCH=CH(CH 2) q, m is that 0,1,2 or 3, two q is 0, or one be 0, another is 1.
Z is
Figure 881036994_IMG99
R wherein 9Be hydrogen or C 1-3Alkyl.Form with free acid exists, or exists with the form of its ester or β-lactone, or with these compounds that the form of suitable salt exists, it is said to can be used as reducing blood fat protein agent and antiatherosclerotic.
Tetrahedron Letters, 29,929,1988 disclose the synthetic of 3-hydroxy-3-methyl-glutaryl CoA-reductase inhibitors with following junction structure:
Wherein R is Na or C 2H 5
European patent application 127,848-A(Merck company) disclose the derivative of 3-hydroxyl-5-thia-omega-aryl-paraffinic acid, its structural formula is as follows:
Wherein Z is:
N is 0,1 or 2;
E is-CH 2-,-CH 2-CH 2-,-CH 2-CH 2-CH 2--CH=CH-CH 2-; Or-CH 2-CH=CH-;
R 1, R 2And R 3Be for example hydrogen, chlorine, bromine, fluorine, C 1The phenyl of-alkyl, phenyl, replacement or OR 7, R wherein 7Be for example hydrogen, C 2-8The phenyl of alkanoyl, benzoyl, phenyl, replacement, C 1-9Alkyl, cinnamyl, C 1-4Haloalkyl, allyl group, cycloalkyl-C 1-3Alkyl, adamantyl-C 1-3-alkyl or phenyl C 1-3Alkyl;
R 4, R 5And R 6Be hydrogen, chlorine, bromine, fluorine or C 1-3Alkyl;
X is for example hydrogen, C 1-3Alkyl, alkali-metal positively charged ion, or be ammonium.
These compounds are owing to suppressing 3-hydroxy-3-methylglutaric acid list acyl coenzyme A(HMG-CoA) reductase enzyme has anti-high blood cholesterol activity; These compounds also have anti-mycotic activity.
The french patent application 2,596 that on April 1st, 1986 submitted to, 393A(Sanofi SA) the 3-carboxyl-2-hydroxy propane phosphonate derivative that comprises its salt is disclosed, these derivatives can be used as lipid-lowering agent and have following formula:
R wherein 1And R 2=H, low alkyl group or the aralkyl that replaces arbitrarily;
R 3And R 4=H, low alkyl group or the aryl or aralkyl that replaces arbitrarily.
Disclosed these compounds can reduce the level of cholesterol, triglyceride level and phosphatide to a greater degree than meglutol.
European patent application 142,146-A(Merck company) compound that is similar to mevinolin is disclosed, its structural formula is:
Figure 881036994_IMG104
Wherein:
R 1For, for example hydrogen or C 1-4Alkyl;
E is-CH 2CH 2,-CH=CH-or-(CH 2) r-;
Z is
1）
Wherein, X be-O-or-NR 9, R wherein 9Be hydrogen or C 1-3Alkyl;
R 7Be C 2-8Alkyl;
R 8Be hydrogen or CH 3;
2）
Wherein, R 10, R 11And R 12Be respectively, for example hydrogen, halogen or C 1-4Alkyl;
3）
Figure 881036994_IMG107
Wherein, n is 0-2, R 14Be halogen or C 1-4Alkyl; Perhaps
4）
Figure 881036994_IMG108
These compounds are the HMG-CoA reductase inhibitor.
According to the present invention, some P contained compounds are provided, these compounds can suppress 3-hydroxy-3-methylglutaric acid list acyl coenzyme A reductase enzyme (HMG-CoA reductase enzyme), thereby can be used as hypocholesterolemic agents.Contain following part in these compounds:
Figure 881036994_IMG109
Wherein, X is-(CH 2) a-,-CH=CH-,-C ≡ C-or-CH 2O-(wherein O links to each other with Z), " a " is 1,2 or 3, Z is one " hydrophobic conjugated group (hydrophobic anchor) ".
Hydrophobic conjugated group one speech is used to refer to a lipophilic group here, this group is when linking to each other with the top side chain that is similar to HMG of this molecule by suitable linking group (" X "), can combine with the hydrophobic capsule of bound substrates HMG COA of not being used on the enzyme molecule, thereby cause the drug effect stronger than the compound of those Z=H.
In preferred embodiments, compound of the present invention has the formula I and comprises its pharmacy acceptable salt:
Figure 881036994_IMG110
Wherein, R is OH or lower alkoxy;
R XBe H or low alkyl group;
X is CH 2,-CH 2CH 2-, CH 2CH 2CH 2-,-CH=CH-,-C ≡ C-or-CH 2O-(wherein O links to each other with Z);
Z is a hydrophobic conjugated group;
Term " salt " refers to the subsalt with mineral alkali and organic bases formation.This class salt comprises ammonium salt, an alkali metal salt such as lithium, sodium and sylvite (these salt are preferred), alkaline earth salt such as calcium and magnesium salts; With the salt of organic bases formation such as the salt of aminated compounds, as dicyclohexyl amine salt, Benzathini Benzylpenicilinum, N-methyl D-glycosamine, Kazakhstan amine salt; Salt with formation such as amino acid such as arginine, Methionins.Preferred nontoxic, pharmacy acceptable salt, but some other salt also can be used for for example isolated or purified process of product.
According to the present invention, the example of the hydrophobic conjugated group that can comprise includes, but is not limited to:
Figure 881036994_IMG111
Figure 881036994_IMG112
Wherein the dotted line representative also can be two keys, for example,
Figure 881036994_IMG113
R wherein 1, R 2, R 2aAnd R 2bCan be identical or different, be selected from the phenyl or the OR of H, halogen, low alkyl group, haloalkyl, phenyl, replacement respectively y, R wherein yPhenyl-low alkyl group for H, alkanoyl, benzoyl, phenyl, halogenophenyl, phenyl-low alkyl group, low alkyl group, cinnamyl, haloalkyl, allyl group, cycloalkyl-low alkyl group, adamantyl-low alkyl group or replacement.
When Z is following formula
R 5And R 5' identical or different, be H, low alkyl group or OH;
R 6Be low alkyl group Or aryl CH 2-;
R 6aBe low alkyl group, hydroxyl, oxo or halogen; Q is 0,1,2 or 3,
R 7Be H or low alkyl group.
When Z is following groups,
Figure 881036994_IMG117
R 3And R 4In one be , another is low alkyl group, cycloalkyl or phenyl-(CH 2) p, p is 0,1,2,3 or 4;
R wherein 13Be hydrogen, low alkyl group, lower alkoxy (except the tert.-butoxy), halogen, phenoxy group or benzyloxy;
R 14Be hydrogen, low alkyl group, lower alkoxy, halogen, phenoxy group or benzyloxy;
R 14aBe hydrogen, low alkyl group, lower alkoxy or halogen;
Supplementary condition are to work as R 13During for hydrogen, R 14And R 14aAll must be hydrogen; Work as R 14During for hydrogen, R 14aBe necessary for hydrogen; R 13And R 14There is one to be trifluoromethyl at the most; R 13And R 14There is one to be phenoxy group at the most; R 13And R 14There is one to be benzyloxy at the most;
R 8Be hydrogen, C 1-4Alkyl, C 3-6Cycloalkyl, C 1-4Alkoxyl group (except the tert.-butoxy), trifluoromethyl, fluorine, chlorine, phenoxy group or benzyloxy; R 9Be hydrogen, C 1-3Alkyl, C 1-3Alkoxyl group, trifluoromethyl, fluorine, chlorine, phenoxy group or benzyloxy, supplementary condition are, work as R 8During for hydrogen, R 9Be necessary for hydrogen; R 8And R 9There is one to be trifluoromethyl at the most; R 8And R 9There is one to be phenoxy group at the most; R 8And R 9There is one to be benzyloxy at the most.
R 10And R 11Be selected from respectively hydrogen, alkyl, cycloalkyl, adamantyl-1 or
Figure 881036994_IMG119
R wherein 13, R 14And R 14aAs above limit q=0,1,2,3 or 4.
Y is O, S or N-R 10
When Z is following group,
Figure 881036994_IMG120
R aBe hydrogen or uncle or secondary 1-6C alkyl;
R bBe uncle or secondary 1-6C alkyl;
Or R a+ R bBe (CH 2) r or (suitable)-CH 2-CH=CH-CH 2;
R=2,3,4,5 or 6;
R 12Be low alkyl group, the group of cycloalkyl or following formula:
Figure 881036994_IMG121
R wherein 8, R 9, R 13, R 14, and R 14aAs above limit.
When Z was following group, X can only be-CH 2-,-CH 2CH 2-or-CH 2CH 2CH 2
Figure 881036994_IMG122
R 15And R 16All be H, Cl, Br, CN, CF 3, phenyl, 1-4C alkyl, 2-8C carbalkoxy ,-CH 2OR 17Or-CH 2OCONHR 18;
R 17Be H or 1-6C alkanoyl;
R 18For alkyl or by any phenyl that replaces of F, Cl, Br or 1-4C alkyl;
Perhaps, R 15And R 16Be together-(CH 2) s-,-CH 2OCH 2-,-CON(R 19) CO-or-CON(R 20) N(R 21) CO-;
S=3 or 4;
R 19=H, 1-6C alkyl, phenyl or benzyl;
R 20And R 21Be H, 1-4C alkyl or benzyl.
When Z is following group,
Figure 881036994_IMG123
R 22For low alkyl group, cycloalkyl, adamantyl-1 or
Figure 881036994_IMG124
T=1,2,3 or 4;
R 23And R 23aIdentical or different, be selected from hydrogen, low alkyl group, lower alkoxy (except the tert.-butoxy), halogen, phenoxy group or benzyloxy respectively;
Supplementary condition are, work as R 23During for hydrogen, R 23aBe necessary for hydrogen; R 23And R 23aThere is one to be trifluoromethyl at the most; R 23And R 23aThere is one to be phenoxy group at the most; R 23And R 23aThere is one to be benzyloxy at the most.
When X is-CH 2During O-(carbon is connected in P, and O is connected in Z), hydrophobic conjugated group Z will be a phenyl or naphthalene type conjugated group, for example:
Figure 881036994_IMG125
Like this, formula I compound comprises:
Figure 881036994_IMG126
Figure 881036994_IMG127
When term " low alkyl group " or " alkyl " here use separately or use as the part of other groups, comprise that normal chain contains 1-12 carbon, be preferably the straight chain and the branched hydrocarbyl of 1-7 carbon, as methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, isobutyl-, amyl group, hexyl, isohexyl, heptyl, 4,4-dimethyl amyl group, octyl group, 2,2, the 4-tri-methyl-amyl, nonyl, decyl, undecyl, dodecyl, various branched chain isomers of these groups or the like, and comprise the halogen substituting group, as F, Br, Cl or I or CF 3, alkoxy substituent, aryl substituent, alkyl-aryl substituent, halogenated aryl substituting group, naphthenic substituent, alkyl-naphthenic substituent, hydroxyl, alkylamino substituting group, alkanoyl amido substituting group, aryl carbonyl amino substituting group, nitro substituent, cyano group substituting group, substituent this class alkyl of thiol substituting group or alkylthio.
When term " cycloalkyl " here uses separately or uses as the part of other group, comprise and contain 3-12 carbon, the saturated cyclic of best 3-8 carbon, comprise cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, the ring octyl group, ring decyl and cyclo-dodecyl, all available following groups of the arbitrary group in these groups replaces: 1 or 2 halogen, 1 or 2 low alkyl group, 1 or 2 lower alkoxy, 1 or 2 hydroxyl, 1 or 2 alkylamino, 1 or 2 alkanoyl amido, 1 or 2 aryl carbonyl amino, 1 or 2 amino, 1 or 2 nitro, 1 or 2 cyano group, 1 or 2 thiol, and/or 1 or 2 alkylthio.
Term " aryl " or " Ar " are used to refer to monocycle or the Bicyclic group that contains 6-10 carbon in its loop section here, as phenyl, naphthyl, the phenyl that replaces or the naphthyl of replacement, wherein the substituting group on the phenyl or naphthyl can be 1,2 or 3 low alkyl groups, halogen (Cl, Br or F), 1,2 or 3 lower alkoxies, 1,2 or 3 hydroxyls, 1,2 or 3 phenyl, 1,2 or 3 alkanoyloxies, 1,2 or 3 benzoyloxys, 1,2 or 3 haloalkyls, 1,2 or 3 halogenophenyls, 1,2 or 3 allyl groups, 1,2 or 3 cycloalkylalkyls, 1,2 or 3 adamantyl alkyl, 1,2 or 3 alkylaminos, 1,2 or 3 alkanoyl amidos, 1,2 or 3 aryl carbonyl aminos, 1,2 or 3 amino, 1,2 or 3 nitros, 1,2 or 3 cyano group, 1,2 or 3 thiol, and/or 1,2 or 3 alkylthios, aryl preferably contain 3 substituting groups.
When term " aralkyl ", " arylalkyl " or " aryl lower alkyl " use separately or use as the part of other group, refer to have the aforesaid low alkyl group of an aryl substituent, for example benzyl here.
When term " lower alkoxy ", " alkoxyl group " or " aryloxy " or " aralkoxy " use separately or use as the part of other group, comprise all above-mentioned low alkyl group, alkyl, aralkyl or aryl that are connected on the Sauerstoffatom here.
When term " lower alkylthio ", " alkylthio ", " arylthio " or " aromatic alkylthio " use separately or use as the part of other group, comprise all above-mentioned low alkyl group, alkyl, aralkyl or aryl that are connected on the sulphur atom here.
When term " lower alkyl amino ", " alkylamino ", " virtue is amino ", " aryl alkane amino " use separately or use as the part of other group, comprise all above-mentioned low alkyl group, alkyl, aryl or aralkyls that are connected on the nitrogen-atoms here.
Term " alkanoyl " is here as the part of other group and when using, refer to be connected in a low alkyl group on the carbonyl.
Term " halogen " or " halogen " are used to refer to chlorine, bromine, fluorine, iodine and CF here 3, preferred chlorine or fluorine.
Preferred those have the formula I compound of following structure:
Figure 881036994_IMG128
Wherein R is OH, OLi or CH 3O; R XBe Li or H;
X is-CH 2-,-CH 2CH 2-,-CH 2CH 2CH 2-,-CH=CH-,-C ≡ C-or-CH 2O-; With
Z is
Figure 881036994_IMG129
R wherein 1For phenyl or contain an alkyl and/or the substituent phenyl of halogen,
R 1Be cycloalkylalkyl, cyclohexyl methyl for example,
Perhaps R 1For containing a substituent benzyloxy of halogen;
R 2And R 2aIdentical, be hydrogen, halogen or low alkyl group;
Z can also be preferred
Figure 881036994_IMG130
R wherein 1And R 2Identical with the top qualification of just formula II compound having been done.
Z can also be preferred
Figure 881036994_IMG131
R wherein 3Be phenyl, low alkyl group, cycloalkyl or the phenylalkyl that replaces, R 4Be phenyl, low alkyl group such as sec.-propyl, cycloalkyl or the phenylalkyl that replaces; Perhaps
Z also can be preferred
Figure 881036994_IMG132
R wherein 5Be H, CH 3Or OH, R 6For Or (replacement) phenyl methyl, wherein R 7Be H or CH 3
Z can also be preferred
R wherein 3And R 4Has a phenyl at least, remaining R for phenyl or replacement 3Or R 4Be low alkyl group.
Formula I compound of the present invention can be prepared by following reaction sequence and description thereof.
Figure 881036994_IMG135
Figure 881036994_IMG136
Figure 881036994_IMG137
Figure 881036994_IMG140
Figure 881036994_IMG141
Figure 881036994_IMG142
Figure 881036994_IMG143
Figure 881036994_IMG144
Seen in above-mentioned reaction sequence " A ", formula I compound can prepare by making iodide A carry out the Arbuzov reaction,, adopts standard A rbuzov reaction conditions and step that is, and heating iodide A and phosphorous acid ester III form the phosphonic acid ester IV.
Figure 881036994_IMG147
Then, use two (three silyls) trifluoroacetamides (BSTFA) and TMS bromine successively, handling the solution of phosphonic acid ester IV in inert organic solvents (as methylene dichloride) under inert atmosphere such as the argon gas, make the phosphonic acid ester IV carry out the phosphoric acid ester cracking, form the phosphonic acids V:
Ⅴ
(a kind of new intermediate)
In anhydrous pyridine, handle the phosphonic acids V with lower alkyl alcohol (as methyl alcohol) and dicyclohexylcarbodiimide, make the esterification of phosphonic acids V.Under inert atmosphere such as argon gas, stir the gained reaction mixture, form alkyl alkylphosphonate VI (a kind of new intermediate).Then the phosphonate monoester VI is dissolved in inert organic solvents such as methylene dichloride, benzene or the tetrahydrofuran (THF) (THF), handle with three silyl diethylamides, and under inert atmosphere such as argon gas, stir, will be dissolved in methylene dichloride (or other suitable inert organic solvents) after this mixture evaporation.Gained solution is cooled to temperature in-10 ℃-Yue 0 ℃ of scope approximately, handles with the dimethyl formamide of oxalyl chloride and catalytic, evaporation obtains the thick product of phosphonyl chloride VII (a kind of new intermediate) then.The phosphonyl chloride VII is dissolved among inert organic solvents such as methylene dichloride, benzene, pyridine or the THF, this solution is chilled to-90 ℃-Yue 0 ℃ approximately, temperature in preferably about-85 ℃ of-30 ℃ of scopes, with cold (its temperature range is identical with phosphonyl chloride VII solution) anionic solution-treated of acetylene X lithium, form acetylene phosphinate XI.
Figure 881036994_IMG149
(a kind of new intermediate)
When carrying out above processing, the VII that is adopted: the X mol ratio is about 3: 1-1: 1, be preferably in about 1.5: 1-2: in 1 the scope.Above-mentioned acetylene lithium anion solutions forms by handling the acetylene X with lithium source such as n-Butyl Lithium in hexane or other inert solvents.
Then, available acetylene phosphinate XI such as following preparation all cpds of the present invention.
Acetylene phosphinate XI is converted into acetylene phosphinate I A 1, promptly in a kind of inert organic solvents such as tetrahydrofuran (THF), handle XI with glacial acetic acid and tetrabutylammonium fluoride, make XI carry out the silyl ether cracking, form ester I A 1
Then can be with I A 1Be hydrolyzed into corresponding subsalt or acid, i.e. R wherein XBe R Xa, R XaBe ammonium, basic metal, alkaline-earth metal, amine etc., method for hydrolysis is as follows: in 25 ℃, under inert atmosphere such as argon gas, handle I A with highly basic such as lithium hydroxide in the presence of Zai diox, tetrahydrofuran (THF) or other inert organic solvents 1The alkali that adopts: ester IA 1Mol ratio is about 1: 1-1.1: in 1 the scope, to form corresponding subsalt
Then can be with chemical compounds I A 2Handle with strong acid such as HCl, form corresponding sour I A 3
Figure 881036994_IMG152
Can be by under 50-60 ℃, handling ester I A with highly basic 1, with ester I A 1Change corresponding secondary salt into, form I A 4
Figure 881036994_IMG153
The alkali that adopts: ester I A 1Mol ratio is about 2: 1-4: in 1 the scope.
Can make secondary salt I A by handling with strong acid such as HCl 4Be converted into corresponding acid, form sour I A.
X of the present invention forms by making acetylene phosphinate XI carry out selective reduction for the phosphinic compounds of (suitable)-CH=CH-is I B, for example, in the presence of reducing catalyst such as palladium-carbon, palladium-barium carbonate and inert organic solvents such as methyl alcohol, uses H 2Handle XI, form the silyl ether XII
(a kind of new intermediate)
The silyl ether XII can be as above-mentioned silyl ether cracking and hydrolysis, the formation ester I B of carrying out 1, subsalt I B 2, sour I B 3, two substituting metal salt I B 4And corresponding diacid I B.
Figure 881036994_IMG155
Figure 881036994_IMG156
X of the present invention is-CH 2-CH 2-phosphinate compounds be ID, form by making acetylene phosphinate XII carry out catalytic reduction.For example, in the presence of reducing catalyst such as carbon-palladium and inert organic solvents such as methyl alcohol, with 50 pounds/inch 2H 2Handle XII, form silyl ether X III
(a kind of new intermediate)
Silyl ether X III can be as above-mentioned silyl ether cracking and hydrolysis, the formation ester I D of carrying out then 1, subsalt I D 2, sour I D 3, secondary salt I D 4, and corresponding diacid I D.
Figure 881036994_IMG158
Referring now to reaction sequence " B ",, in some formula I compound, the X linking group between phosphorus atom and the hydrophobic conjugated group Z is (instead)-CH=CH-, and these compounds can followingly be prepared.Use a kind of radical initiator,, handle acetylene X and positive C as Diisopropyl azodicarboxylate (AIBN), hydrogen peroxide, benzoyl peroxide etc. 4H 9The mixture of SnH is heated to temperature in about 100-140 ℃ scope with gained solution under inert atmosphere such as argon gas, form vinyl stannane X V.
Figure 881036994_IMG159
Vinyl stannane X V is dissolved in a kind of organic solvent such as ether, methylene dichloride or the chloroform, uses iodinate, and under inert atmosphere such as argon gas, stir, form vinyl iodide X VI.
Figure 881036994_IMG160
With the solution of vinyl iodide X VI in anhydrous organic solvent such as tetrahydrofuran (THF) or ether freezing (78-40 ℃), handle with the n-Butyl Lithium that a kind of metal replaces in reagent such as the inert organic solvents (as hexane).This mixture is cooled under inert atmosphere such as argon gas-78-40 ℃.This negatively charged ion is added in the solution of refrigerative (78-40 ℃) phosphonyl chloride VII in anhydrous inert organic solvent such as tetrahydrofuran (THF) or ether, adds fashionable X VI: the VII mol ratio at about 1: 1 to about 2: 1 scope, preferably from about 1: 1 to about 1.5: 1.So just, form silyl ether X VII
(a kind of new intermediate)
Make silyl ether X VII carry out the silyl ether cracking with the following method.With glacial acetic acid and (just-C 4H 9) 4The solution of NF in inert organic solvents such as tetrahydrofuran (THF) is handled the solution of compound X VII in inert organic solvents such as tetrahydrofuran (THF) or acetonitrile; Form hydroxyl diester I C 1
Can make diester I C as mentioned above then 1Hydrolysis.Form subsalt I C 2, sour I C 3, subsalt I C 4, and corresponding diacid I C.
Figure 881036994_IMG163
Figure 881036994_IMG164
Shown in reaction sequence " C ", in another approach, available following method prepares some formula I compound, and in these compounds, the X linking group between phosphorus atom and the hydrophobic conjugated group Z is (instead)-CH=CH-.In the presence of a kind of organic solvent such as tetrahydrofuran (THF) or ether, make the aldehyde VIII
Figure 881036994_IMG165
With refrigerative (90-0 ℃) dialkyl methyl phosphonate and butyllithium (LiCH 2The PO(alkyl) 2) solution carry out condensation reaction, form beta-hydroxy phosphonic acid ester XX
Figure 881036994_IMG166
Then, in the presence of benzene or toluene, handle beta-hydroxy phosphonic acid ester XX, (be preferably in and reflux down) simultaneously and be heated to the temperature in about 50-120 ℃ scope with tosic acid, thus elimination water and form trans olefins X XI.
Figure 881036994_IMG167
In the presence of Zai diox or other inert organic solvents, with alkali metal hydroxide for example the aqueous solution of LiOH handle compound X XI and make it hydrolysis, handle formation one acid esters X XII with sour example hydrochloric acid then.
Figure 881036994_IMG168
Handle the solution of an acid esters X XII in anhydrous methylene chloride with three silyl diethylamides.Evaporate this mixture, gained oily matter, is handled with the dimethyl formamide of oxalyl chloride and catalytic amount under inert atmosphere such as argon gas with the anhydrous methylene chloride dissolving that is cooled to 0 ℃, forms phosphonyl chloride X XII.
Figure 881036994_IMG169
In the presence of-90-40 ℃ low temperature and a kind of inert organic solvents such as tetrahydrofuran (THF), make phosphonyl chloride XX III and Acetacetic acid alkyl ester dianion, carry out condensation as the methyl acetoacetate dianion, used phosphonyl chloride: the dianion mol ratio is about 1: 1-0.75: in 1 the scope, thereby form one phosphonic acids ester XX IV.
(a kind of new intermediate)
In the presence of a kind of alkanol such as ethanol, handle compound XX IV with a kind of reductive agent such as sodium borohydride and make it reduction, form phosphinate I C 1,
Figure 881036994_IMG171
Then can be as the above-mentioned diester I C that makes 1Hydrolysis forms subsalt I C 2, sour I C 3, secondary salt I C 4And corresponding diacid I C.
Figure 881036994_IMG173
Referring to reaction sequence D, some formula I compound can be prepared with the following method, and in these compounds, X is-(CH 2) a-, a is 1,2 or 3, promptly X is-CH 2-CH 2CH 2-or-CH 2CH 2CH 2-.Initial with the aldehyde VIII, change it into halogenide VIII a with ordinary method.For example, can in the presence of ethanol and ether, use NaBH 4Reduction aldehyde VIII forms corresponding alcohol.
In the presence of a kind of organic bases such as triethylamine and a kind of solvent such as methylene dichloride, handle compound VIII a with methylsulfonyl chloride, form muriate XX V (a=1).
Make muriate XX V carry out condensation reaction, wherein handle the XX V and form phosphonic acid diester XX VI with the phosphorous acid ester III.Used III during processing: XX V mol ratio is about 1: 1-10: in 1 the scope, temperature is in about 100-150 ℃ scope.Handle the solution of phosphonic acid diester XX VI in a kind of solvent such as diox with highly basic such as alkali metal hydroxide (for example LiOH), form corresponding monoesters.In the presence of a kind of inert organic solvents such as dimethyl formamide, handle this monoesters, form corresponding phosphonyl chloride XX VII with oxalyl chloride.In the presence of a kind of inert organic solvents such as tetrahydrofuran (THF), under pact-90-40 ℃ low temperature, make XX VII and Acetacetic acid alkyl ester dianion, carry out condensation as the methyl acetoacetate dianion, form ketone phosphinate XX VII.Used phosphonyl chloride XX VII during condensation: the dianion mol ratio is about 1: 1-0.75: in 1 the scope.Ketone phosphinate XX VII is a kind of new intermediate.Then, ketone phosphinate XX VII can be reduced into corresponding phosphinate I D 1, I E 1With I F 1, these compounds can be hydrolyzed and form corresponding diacid I D, I E and I F again by the described step of reaction sequence C.
Referring to reaction sequence E, X is-CH 2The formula I compound of O-can the aldehyde VIII be that starting raw material is prepared.In the presence of a kind of inert organic solvents such as methylene dichloride, make VIII and metachloroperbenzoic acid (MCPBA) reaction, in the presence of highly basic such as alkali metal hydroxide (as KOH or NaOH) and a kind of solvent such as tetrahydrofuran (THF), react then, make the one Villiger oxidation of aldehyde VIII generation Baeyer, form corresponding pure XX IX.In the presence of a kind of inert organic solvents such as dimethyl formamide, under inert atmosphere such as argon gas, with the solution-treated XX IX of sodium hydride and tosyloxy dialkyl methyl phosphonate XXX, make the alkylation of pure XX IX and form corresponding dialkyl XX XI.Used XXX during processing: XX IX mol ratio is about 1: 1-3: in 1 the scope.The described formation monoesters of reaction sequence E XX XII, muriate XXX III, ketone phosphinate XXX IV (a kind of new intermediate), diester I G 1Similar with the synthesis step of diacid I G with the relevant step of previous reaction order D.
Acetylene raw material X can be prepared by corresponding aldehyde VIII,
Even VIII is carried out witig reaction.For example, with tetrabromomethane (CBr 4) solution in a kind of inert organic solvents such as methylene dichloride, handle refrigerative (25 ℃-0 ℃) solution of VIII in triphenyl phosphine and a kind of inert organic solvents such as methylene dichloride, form vinyl dibromo IX.
Figure 881036994_IMG176
Under inert atmosphere, in inert organic solvents such as hexane, handle the compound IX with n-Butyl Lithium, make it dehydrohalogenation and obtain X.
Under inert atmosphere, in the presence of the potassium tert.-butoxide in inert organic solvents such as tetrahydrofuran (THF) (78 ℃-25 ℃), handle the aldehyde VIII with the dizaomethyl dimethyl phosphonate, also can make the aldehyde VIII directly be transformed into the acetylene X.
The iodide raw material A can at first prepare from bromide C.
Figure 881036994_IMG177
(utilize, 2951(1985) described in method preparation) at Tetrahedron Lett.26
Bromide C is dissolved in the solution of dimethyl formamide (DMF) and imidazoles and 4-Dimethylamino pyridine, under inert atmosphere such as argon gas, handles gained solution, form silyl ether D with t-butyldiphenylsilyl chlorine.
Figure 881036994_IMG178
Under inert atmosphere such as argon gas, handle the solution of silyl ether D in inert organic solvents such as methyl ethyl ketone or DMF with sodium iodide, form iodide A.
Raw material aldehyde cpd VIII, promptly
Figure 881036994_IMG179
Be known compound.
Various intermediate IV, V, VI, VII, XI, XII, X III, X VII and XX IV also are parts of the present invention.These new intermediates can be represented with following general formula XXX V and XXX VI:
Comprise its all steric isomers, wherein R 1 aBe alkoxyl group or hydroxyl, R 1 bFor alkoxyl group, hydroxyl, Cl ,-CH 2-Z ,-CH 2CH 2CH 2-Z ,-CH 2O-Z ,-C ≡ C-Z ,-CH=CH-Z ,-CH 2CH 2-Z, wherein Z is a hydrophobic as defined above conjugated group; Condition is R 1 bDuring for hydroxyl, R 1 aBe preferably hydroxyl or alkoxyl group;
Figure 881036994_IMG181
Wherein Z as above limits, and comprises its all steric isomers.
Compound of the present invention can be prepared into racemic mixture, then can split and obtains preferred S-isomer.But also can be as herein and as described in the embodiment after this, directly the form with its S-isomer prepares compound of the present invention.
Such as following experiment confirmation, compound of the present invention is the inhibitor of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase enzyme, thereby can be used for suppressing the cholesterol biosynthesizing.
1) rats'liver HMG-CoA reductase enzyme
Measure rats'liver HMG-CoA reductase activity (Edwards, P.A. etc., J.Lipid Res.20: 40,1979) with the described method of the Edwards that revises.Do the enzyme source with rat liver microsomes, by measuring 14C-HMG-CoA extremely 14Enzymic activity is determined in the conversion of C-mevalonic acid.
A, MC preparation
After decaptitating, the Sprague Dawley rat that only fed QUESTRAN with 2-4 gets liver, at phosphoric acid buffer A(potassiumphosphate, 0.04M, pH7.2; KCl, 0.05M; Sucrose, 0.1M; EDTA, 0.03M; Trypsin inhibitor,Trasylol, the 500KI units per ml) middle homogenate.In 4 ℃ with homogenate centrifugal 15 minutes with 16,000 * g.Shifting out supernatant liquor, to carry out the second time under similarity condition centrifugal.In 4 ℃ of following 16,000 * g supernatant liquors centrifugal 70 minutes for the second time with 100,000 * g.Settled microsome is suspended in again in the buffer A of minimum volume (each liver 3-5 milliliter) homogenate in the glass-glass homogenizer.Add dithiothreitol (DTT) (10mM), this prepared product is divided into some equal portions, quick freezing in acetone/dry ice is stored down in-80 ℃.The ratio work of first microsome prepared product be 0.68 nanomole mevalonic acid/milligram albumen/minute.
B, enzymatic determination
In 0.25 milliliter of reaction solution, measure reductase enzyme, contain the following composition of specifying final concentration in the reaction solution:
0.04M potassiumphosphate, pH7.0
0.05M KCl
0.10M sucrose
0.03M EDTA
0.01M dithiothreitol (DTT)
3.5mM NaCl
1% methyl-sulphoxide
50-200 microgram microsomal protein
100μM 14C-〔DL〕HMG-CoA（0.05
Microcurie, 30-60 millicurie/mmole)
2.7mM NADPH(Triphosphopyridine nucleotide, reduced
Salt)
Reaction mixture is in 37 ℃ of insulations down.Under these conditions, when containing microsomal protein reaching 300 micrograms in every part of reaction mixture, enzyme activity is linear to be increased, and concerning soaking time, in the time of 30 minutes, enzyme activity is linear.The selected standard soaking time of drug test is 20 minutes, and this HMG-CoA substrate conversion that can cause 12-15% is the mevalonic acid product.The concentration of used (DL) HMG-CoA substrate is 100 μ M, doubles and makes the saturated required concentration of enzyme under these conditions.Used NADPH is excessive, and its concentration is to reach 2.7 times of maximum enzyme speed of response desired concn.
Carry out the stdn test that inhibitor is measured by following method.Microsomal enzyme is incubated 15 minutes in 37 ℃ in the presence of NADPH.Add the DMSO matchmaker's liquid that contains or do not contain testing compound, this mixed solution is incubated 15 minutes again in 37 ℃.Add 14The C-HMG-CoA substrate starts enzymatic determination.After 20 minutes, add 25 microlitre 33%KOH termination reactions in 37 ℃ of insulations.Add 3H-mevalonic acid (0.05 microcurie) was placed reaction mixture 30 minutes under room temperature.Add 50 microlitre 5N HCl and make mevalonolactoneization.Add tetrabromophenol sulfonphthalein and make the pH indicator, with the suitable reduction of monitoring pH.Lactonization reaction was at room temperature carried out 30 minutes.With reaction mixture centrifugal 15 minutes with 2800rpm.Supernatant liquor is layered on is contained in the 0.7cm(internal diameter) on the 2 gram AG1-X8 anionite-exchange resin in the glass column (Biorad, formic acid type), with 2.0 milliliters of H 2The O wash-out.Discard 0.5 milliliter, collect back 1.5 milliliters, in 10.0 milliliters of Optifluor scintillation solutions, deuterium and carbon 14 are counted.Calculate the nanomole number that produced mevalonic acid in per 20 minutes, and the rate of recovery that this result is corrected to deuterium is reached 100%.Drug effect is with I 50Value (making the enzyme life birth give birth to 50% drug level that suppresses) expression, this value is to draw from the recombiner quantitative response data with specified 95% fiducial interval.
Make the medicine of lactone form change its sodium salt into by the following method: this lactone of dissolving in DMSO, add the excessive 10 times NaOH of mole number, mixed solution was placed under room temperature 15 minutes.Then this mixed solution is partly neutralized (pH7.5-8.0) with 1N HCl, it is diluted in the enzyme reaction mixed solution.
2) cholesterol in the rat hepatocytes of fresh separated is synthetic
Utilize at first by the described method of people such as Capuzzi (Capuzzi, D.M.and Margolis, S., Lipids, 6: 602,1971), measure those compounds that show the HMG-CoA reductase active in the suspension of the rat hepatocytes of fresh separated, right 14The C-acetate mixes the inhibition ability of cholesterol.
The separation of a, rat hepatocytes
Get Sprague Dawley rat (180-220 gram) and use the Nembutol(50 mg/kg) anesthesia.Open the abdominal cavity, pylic first branch of ligation.(100-200 unit) is injected directly into abdominal vein with heparin.On pylic distal part, be equipped with a single line so that ligation is made venous cannula between this suture and first branch's vein.After cutting off abdominal vein, with (37 ℃) of preheating, carry out liver perfusion with the flow velocity of 20 ml/min, make the effluent liquid discharge with oxygen-saturated buffer A (no calcium or magnesium also contain the HBSS of 0.5mMEDTA).Use the buffer B (HBSS that contains 0.05% bacterial collagenase) of 200 milliliters of preheatings to carry out liver perfusion again.After the buffer B perfusion, liver is cut, place 60 milliliters of Waymouth media to remove tunicle, the free cell is dispensed in the medium.At room temperature with 3 minutes isolating hepatocytes of 50 * g low-speed centrifugal.Settled liver cell is washed once in the Waymouth medium, and counting also detects its surviving rate with trypanblue exclusion method.These are rich in the surviving rate that hepatocellular cell suspending liquid has 70-90% usually.
B, 14The C-acetate is incorporated in the cholesterol
With liver cell with per 2.0 milliliter 5 * 10 6The concentration of individual cell is suspended in (0.02M Tris-HCl(pH7.4), 0.1M KCl, 3.3mM Trisodium Citrate, 6.7mM niacinamide, 0.23mM NADP, 1.7mM G-6-P in the thermal insulation medium (IM)).
Test compound is dissolved in DMSO or DMSO: H routinely 2O(1: 3), add among the IM then.The final concentration of DMSO≤1.0% among the IM is to the synthetic not obviously influence of cholesterol.
Add 14C-acetate (58 millicuries/mmole, 2 microcurie/milliliters) started insulation reaction, and cell suspending liquid (2.0 milliliters) is placed 35 millimeters tissue culture wares, in 37 ℃ of insulations 2.0 hours.After the insulation, cell suspending liquid is moved in the glass centrifuge tube at room temperature centrifugal 3 minutes with 50 * g.Cell precipitation is suspended in 1.0 milliliters of H again 2Make it dissolving among the O, and place ice bath.Basically press Bligh, the described method of E.G. and W.J.Dyer (Can.J.Biochem.and Physiol., 37: 911,1959) extraction lipid.Shift out the bottom organic phase, dry under nitrogen gas stream, with the residue resuspending in (100 microlitre) chloroform: in the methyl alcohol (2: 1).With entire sample point on silica gel (LK6D) thin layer plate, at hexane: ether: exhibition layer in the acetate (75: 25: 1).With the BioScan automatic scanning system thin layer plate is scanned and counts.Measure the radio-labeled in the cholesterol peak (RF0.28), recently represent with the percentage of mark in the grand total at each peak and the whole lipid extract.The cholesterol peak of control cultures contains 800-1000cpm usually, is the 9-20% of whole lipid extract mark.People's such as this and Capuzzi result is similar, and their result shows that being marked with of extraction 9% is present in the cholesterol.
The compare culture and in the culture cholesterol of drug treating the per-cent of mark, determine drug effect (the synthetic per-cent that suppresses of cholesterol).Set up dose response curve by the data splitting from two or more experiments, the result is to have the I of 95% fiducial interval 50Value representation.
3) cholesterol in the human skin fibroblast is synthetic
Tending to have in hepatic tissue the active compound selective of higher inhibition, should be a feature of cholesterol synthesis inhibitor.Therefore, except in liver cell, measuring cholesterol synthesis inhibitor, also detected these compounds activity as cholesterol synthesis inhibitor in the inoblast of cultivating.
A, human skin fibroblast are cultivated
In containing the Eagles MEM (EM) of 10% foetal calf serum, cultivator skin flbroblast (7-27 goes down to posterity).In each experiment, with the cell dispersion individual layer, be layered in 35 millimeters tissue culture wares (5 * 10 behind the counting with trysinization storage culture 5Individual cell/2.0 milliliter).Culture under 37 ℃ at 5%CO 2Cultivated 18 hours in/95% wet air.Remove the substratum that contains serum, the washed cell individual layer adds 1.0 milliliters of EM that contain 1.0% FAF bovine serum albumin(BSA), culture is cultivated 24 hours again, thereby induce the cholesterol biosynthesis enzyme class.
B, 14The C-acetate mixes cholesterol
With the fibroblast cell cultures EMEM after inducing 100(Eearle MEM) washing.Test compound is dissolved in DMSO or DMSO: EM(1: 3) (final concentration of DMSO≤1.0% in the cell culture), add to then in the culture, this culture under 37 ℃ at 5%CO 2Pre-incubation is 30 minutes in/95% wet air.After adding the medicine pre-incubation, add (1- 14C) sodium acetate (2.0 microcurie/milliliters, 58 millicuries/mmole), culture is incubated 4 hours again.After the insulation, remove substratum, cell monolayer (every part of culture 200 microgram cell proteins) is scraped into 1.0 milliliters of H 2Among the O.As described in to hepatocyte suspension, use chloroform: the lipid in the methanol extraction dissolved cell suspending liquid.Organic phase is dry under nitrogen, with the residue resuspending in chloroform: in the methyl alcohol (2: 1) (100 microlitre), entire sample point on silica gel (LK6D) thin layer plate, is analyzed as described in to liver cell.
By compare culture and the mark per-cent in the cholesterol peak of the culture of drug treating, determine that the cholesterol synthetic suppresses.The result is with I 50Value representation, this is to release from the compound dose response curve from two or more experiments.I 5095% fiducial interval of value is also by recombiner quantitative response curve calculation.
Of the present invention is a kind of medicinal compositions more on the one hand, and said composition contains at least a formula I compound and combines with a kind of pharmaceutical carrier or thinner.The medicinal additive that this medicinal compositions can utilize conventional solid or liquid support or thinner and its type to be suitable for required administering mode is prepared.These compounds can oral administration, for example with tablet, capsule, granula or powder form administration; Perhaps with the form of injectable formulation by the parenteral route administration, when this formulation was used for the treatment of, every dose contained 1-2000 milligram active compound.Dosage depends on single dose, patient's symptom, age and body weight.
In Mammals such as people, dog, cat etc., formula I compound can be used with the mode similar to recommending to be used to suppress biosynthetic known compound of cholesterol such as lovastatin.Therefore the amount of application of compound of the present invention can be an about 4-2000 milligram of single dose; Or, being preferably the 4-200 milligram with form every day of individual dose 1-4 time, fractionated dose is the 1-100 milligram; Suitable is every day 2-4 time, 0.5-5 milligram at every turn; Or form to continue to discharge.
Following example is better embodiment of the present invention, and except that other indicated, temperature all adopted a degree centigrade expression, and flash chromatography carries out on Merck 60 or Whatmann LPS-I silica gel.Reverse-phase chromatography carries out on the CHP-20MCI gel resin that Ltd. provides at Mitsubishi.
Used abbreviation " Et in following examples 2O " " EtOAC ", " MeoH " and " EtOH " represents ether respectively, ethyl acetate, methyl alcohol and ethanol.Singlet, doublet, triplet, quartet, multiplet, Septet represent unimodal, doublet, triplet, quartet, multiplet, septet respectively in the NMR data.
Embodiment 1
(S)-4-(((4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)-the 2-yl) methoxyl group) the methoxyl group phosphinyl)-3-hydroxyl-butyric acid, methyl esters
A.N-(2, the 4-dimethyl benzylidene) aniline.With reference to the US Patent No of Merck, 4,375,475,39 pages.
New distillatory 2, (Aldrich's 4-dimethylbenzaldehyde produces, 6.97 milliliter, 50 mmoles) and heavily (Aldrich produces to steam aniline, 4.56 milliliter, 50 mmoles) dry toluene (80 milliliters) solution refluxed in the flask that has the Dean-Stark device, under argon gas 3 hours, after the mixture cooling, flash to yellow oil in a vacuum.Thick oil obtains 8.172 gram (78.1%) title benzene group with imine moiety through Kugelrohr distillation purifying (0.5 mmhg, 160-180 ℃) again, is faint yellow oily, leaves standstill and crystallizes into the low melting point solid.TLC(4: 1) hexane-acetone, Rf=0.67 and 0.77(geometrical isomer) ultraviolet and iodine.
With reference to the US Patent No of Merck, 4,375,475,39 pages.
The mixture of the benzene imines that A is partly made (6.0 grams, 28.7 mmoles) and Glacial acetic acid (144 milliliters) is handled with palladium (II, 6.44 grams, 28.7 mmoles).This limpid, red solution uniformly refluxed 1 hour under argon gas.The turbid mixture that obtains is by the thick bed of diatomaceous earth of 1/2 English inch, and heat filtering is in 900 ml waters.Filter collecting precipitation orange solids and 65 ℃ with Vanadium Pentoxide in FLAKES vacuum-drying 16 hours, obtain 10.6 gram (85.5%) title palladium complexs, be orange solids, fusing point 194-196 ℃ (the document fusing point through the analytic sample of recrystallization is 203-205 ℃).
C.4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)-2-formaldehyde
(1) (4-fluoro-3-aminomethyl phenyl) magnesium bromide
With reference to 4,375,475,37 and 38 pages of the U.S. Patent No.s of Merck.
Being prepared as follows of the Grignard reagent of portion C (1) title, with 5-bromo-2-toluene fluoride (22.5 grams, 60.9 mmole, the Fairfield chemical company is produced), be added drop-wise to the speed that is enough to keep to react backflow and stirring, be placed with in the dry ether (70.0 milliliters) of magnesium rod (1.35 grams, 55.4 mmoles, 8 equivalents).Be reflected in the Vltrasonic device and cause.After adding bromide, mixture stirring at room 1 hour under argon gas refluxed 15 minutes, then cool to room temperature.
(2) 4 '-fluoro-3,3 ', the 5-trimethylammonium-(1,1 '-biphenyl)-2-formaldehyde
In another flask, with two palladium complexs (3.0 grams, 6.92 mmoles) and the mixture of triphenylphosphine (14.52 grams, 55.4 mmoles, 8 equivalents) in dry benzene (100 milliliters) that B partly obtains, stirring at room is 30 minutes under argon gas.Freshly prepd C(1) after Bu Fen Grignard reagent filters with the glass fiber plug, joins in the flask by the gross with intubate.Mixture stirring at room 1.5 hours under argon gas.Add 6N hydrochloric acid (35 milliliters), mixture stirring at room 1 hour, filters by the thick bed of diatomaceous earth of 1/2 English inch more then.Filtrate is extracted with ether (250 milliliters), and extracting solution with anhydrous magnesium sulfate drying and vacuum-evaporation, obtains 13.35 gram heavy-gravity orange with salt solution (2 * 100 milliliters) washing, leaves standstill post crystallization.This orange solids crude product is gone up purifying with the flash chromatography method at silica gel (700 gram), use earlier hexane, use the hexane-ether wash-out of (95: 5) again, merge product section, evaporation obtains 1.507 gram (89.9%) title aldehyde cpds, be faint yellow solid, fusing point 72-75 ℃ (73-74 ℃ of reported in literature fusing point).TLC:(95: 5) hexane-ether, R f=0.40, ultraviolet and phospho-molybdic acid (PMA)
D.2-(2, the 2-dibromo vinyl)-4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)
In (10 ℃ of refrigerative, the salt ice bath) the xenyl aldehyde of C part is (242 milligrams, 1.0 mmole) and (787 milligrams of triphenylphosphines, 3 mmoles, 3 equivalents) in dry methylene chloride (10 milliliters) solution, methylene dichloride (5.0 milliliters) solution that dripped carbon tetrabromide (497 milligrams, 1.5 mmoles, 1.5 equivalents) in 5 minutes is handled.At 0 ℃ after 30 minutes, reddish orange solution distributes between methylene dichloride and saturated sodium bicarbonate.Organic phase is used anhydrous sodium sulfate drying again with saturated sodium bicarbonate and salt water washing, obtains the light brown solid of 1.478 grams after the evaporation.Crude product is gone up purifying with the flash chromatography method at silica gel (50: 1), with (9: 1) hexane-methylene dichloride wash-out.Obtain 392 milligrams of (99%) pure title vinyl dibromide after merging the product section evaporation, be light yellow oil.TLC(95: 5) hexane-ethyl acetate, R f=0.51, ultraviolet and phospho-molybdic acid (PMA).
E.2-ethynyl-4 '-fluoro-3,3 ', 5-trimethylammonium-(1,1 '-biphenyl)
In (336 milligrams of the D of-78 ℃ (dry ice/acetone) vinyl dibromide partly, 0.844 in dry tetrahydrofuran mmole) (5 milliliters) solution, be added dropwise to (1.06 milliliters of the hexanes of 1.6M n-Butyl Lithium with syringe, 1.7 mmole, 2.0 equivalent) solution is handled, mixture stirred 1 hour under argon gas at-78 ℃.In the n-Butyl Lithium adition process, change in color from colourless to deep yellow, to pale yellow, again to deep blue purplish red be clearly.Drip saturated ammonium chloride (4 milliliters) in the mixture-78 ℃ of termination reactions, go back up to room temperature, use ether extraction, with salt water washing ether layer, use anhydrous magnesium sulfate drying, evaporation obtains 191 milligrams of green oily matter.Crude product oil is gone up purifying with the flash chromatography method at LPS-1 silica gel (60: 1), uses the hexane wash-out.Merge the product part, evaporation obtains 185 milligrams of (92%) title acetylene compounds, is colorless oil, leaves standstill under-20 ℃ of argon gas, finally becomes avy blue.
The TLC hexane, R f=0.18, ultraviolet and phospho-molybdic acid (PMA)
F.(S)-3-(((1, the 1-dimethyl ethyl) diphenylmethyl silylation)-oxygen)-4-(chlorine methoxyl group phosphinyl)-butyric acid, methyl esters
(1) (S)-4-bromo-3-beta-hydroxymethyl butyrate
(1) (a) (R-(R *, R *))-2,3,4-trihydroxy-butyric acid, calcium salt, hydrate.
With reference to Canbohydrate Research 72, pp.301-304(1979).
In water (625 milliliters) solution of D-saccharosonic acid (44.0 grams, 250 mmoles), add lime carbonate (50 gram), this suspension is cooled to 0 ℃ (ice bath), use 30% hydrogen peroxide (100 milliliters) to handle in batches.Mixture stirred 30 minutes 30-40 ℃ (oil bath).Adding Darco(10 gram) black suspension heats in steam bath, stops to overflow up to oxygen.Suspension is by diatomite filtration, and is warm in steam bath in vacuum-evaporation (bathing 40 ℃ of the temperature) residuum water-soluble (50 milliliters), adds methyl alcohol, until the solution muddiness.Filter and collect gelatinous precipitate, dry air obtains 30.836 gram (75.2%) desired calcium salts, is the white powder solid.
TLC(7: 2: 1) Virahol-ammonium hydroxide-water, R f=0.19, phospho-molybdic acid (PMA)
(1) (b) (S-(R *, S *))-2,4-two bromo-3-hydroxybutyric acids, methyl esters
With reference to Bock, K waits the people, Acta Scandinavica(B) 37, pp.341-344(1983)
(1) (a) calcium salt (30 gram) of part was dissolved in the acetic acid (210 milliliters) that contains 30-32%HBr, stirring at room 24 hours.In this brown solution, stirring is spent the night to add methyl alcohol (990 milliliters).Get orange after the mixture evaporation, be dissolved in the methyl alcohol (75 milliliters), refluxed revaporization 2 hours.Residuum distributes between ethyl acetate (100 milliliters) and water, anhydrous sodium sulfate drying is used in organic phase water (2 times) and salt water washing, and evaporation obtains 22.83 gram (90.5%) dibromo thing crude products, be light orange oily matter, TLC(1: 1) ethyl acetate-hexane, R f=0.69, ultraviolet and phospho-molybdic acid (PMA).
(1) (c) (S)-4-bromo-3-hydroxybutyric acid, methyl esters
With reference to preparation (1) document (b).
Add 5% palladium/carbon (1.30 restrain) processing with being blown in the dibromide (20.80 gram, 75.4 mmoles) of argon gas and the solution that sodium acetate, anhydrous (21.0 gram) is dissolved in ethyl acetate (370 milliliters) and Glacial acetic acid (37 milliliters).This black suspension is led to H 2(1 normal atmosphere) stirs, and monitors H simultaneously 2Be absorbed situation, H after 2 hours 2Absorption is finished, and mixture is by diatomite filtration, and filtrate is used anhydrous magnesium sulfate drying with saturated sodium bicarbonate and salt water washing, and evaporation obtains the dibromo ester crude product, is brown oil.Thick oil merges with another batch product (is starting raw material with 36.77 gram dibromide), vacuum distilling obtains 25.77 gram (61.3%) title bromo-esters, is colorless oil, boiling point 79-80 ℃ (1.0 mmhg), TLC(1: 1) ethyl acetate-hexane, R f=0.44, phospho-molybdic acid (PMA)
Ultimate analysis calculated value: C 5H 9O 3Br:C, 30.48; H, 4.60;
Br，40.56
Measured value: C, 29.76; H, 4.50; Br, 39.86
(2) (S)-and 4-bromo-3-(((1, the 1-dimethyl ethyl)-diphenylmethyl silylation) oxygen) butyric acid, methyl esters
F(1) Bu Fen bromohydrin (4.0 grams, 20.4 azoles miaow (6.94 grams mmole), 5.0 equivalent) and (12 milligrams of 4-dimethylamino pyridines (4-DMAP), 0.005 equivalent) in the solution of dry dimethyl formamide (40 milliliters), with (5.84 milliliters of tert-butyl diphenyl chlorosilanes, 1.1-equivalent) handle this uniform mixture stirred overnight at room temperature under argon gas.Mixture distributes between 5% sal enixum and ethyl acetate, and anhydrous sodium sulfate drying is used in organic phase water and salt water washing, and evaporation obtains 9.32 gram (100%) silicon ether crude products, is colourless thickness oily matter.TLC(3: 1) hexane-ethyl acetate, R f(silicon ether)=0.75, ultraviolet and phospho-molybdic acid (PMA)
(3) (S)-and 4-iodo-3-(((1, the 1-dimethyl ethyl) diphenylmethyl silylation) oxygen) butyric acid, methyl esters
F(2) methyl ethyl ketone of Bu Fen bromide crude product (9.32 gram, 201 mmoles) (60 milliliters, through 4
Figure 881036994_IMG183
Molecular sieve drying) solution is handled with sodium iodide (15.06 grams, 100.5 mmoles, 5.0 equivalents), and yellow suspension refluxed 5 hours under argon gas.After the mixture cooling, with the ethyl acetate dilution, filter, filtrate is washed till colourless with rare sodium bisulfite, the salt washing, and behind anhydrous sodium sulfate drying, vacuum-evaporation obtains 10.17 gram yellow oil.Crude product is gone up purifying with the flash chromatography method at silica gel (600 gram), with (3: 1) hexane-methylene dichloride wash-out.Merge the product part, evaporation obtains 7.691 grams (74.2%, two step overall yield) title iodide, is limpid, colourless, thickness oily matter.TLC(3: 1) hexane-ethyl acetate, product R f=0.75, ultraviolet and phospho-molybdic acid (PMA) (note: product iodide and initial bromide be spot altogether).
(4) (S)-4-(diethoxy phosphinyl)-3-(((1, the 1-dimethyl ethyl) quadrosilan base) oxygen)-butyric acid, methyl esters
Triethyl-phosphite (20 milliliters) solution of iodide (7.691 gram) is 155 ℃ (oil baths), argon gas heated 3.5 hours down, mixture cooling, vacuum distilling are removed excessive phosphorous acid ester (0.5 mmhg, 75 ℃) and are stayed yellow oil (about 8.0 grams).Crude product is gone up purifying with the flash chromatography method at silica gel (400 gram), with (4: 1) hexane-acetone wash-out.The product part obtains 3.222 gram (41.1%) title phosphinates through evaporation, is limpid, colourless, thickness oily matter.TLC(1: 1) hexane-acetone, R f=0.51, ultraviolet and phospho-molybdic acid (PMA).In addition, reclaimed 2.519 grams (revising productive rate 61.1%) initiator, the iodide of (3) part.
(5) (S)-and 3-(((1, the 1-dimethyl ethyl) quadrosilan base) oxygen)-4-phosphono butyric acid, methyl esters
F(4) Bu Fen phosphinate (9.85 grams, 20.0 dry methylene chloride mmole) (20 milliliters) solution is used (5.31 milliliters of two three silyl trifluoroacetamides (BSTFA) successively, 32.0 mmole, 1.6 equivalent) and (6.60 milliliters of bromotrimethylsilanes (TMSBr), 50.0 mmole, 2.5 equivalent) handle, limpid mixture is stirred overnight at room temperature under argon gas.Add 5% sal enixum (80 milliliters), the mixture ethyl acetate extraction.Water is saturated with sodium-chlor, extracts with ethyl acetate again.Merge organic layer, use the salt water washing, behind anhydrous sodium sulfate drying, vacuum-evaporation obtains title phosphonic acids crude product, is thickness oily matter, TLC(7: 2: 1) Virahol-ammonium hydroxide-H 2O, R f=0.30, ultraviolet and phospho-molybdic acid (PMA).
(6) (S)-3-(((1, the 1-dimethyl ethyl) quadrosilan base) oxygen)-4-(hydroxyl methoxyl group phosphinyl)-butyric acid, methyl esters
F(5) Bu Fen phosphonic acids crude product (about 20.0 mmoles) is dissolved in the exsiccant pyridine (25 milliliters), uses exsiccant methyl alcohol (through 3 Molecular sieve is handled, and 1.62 milliliters, 40.0 mmoles, 2.0 equivalents) and dicyclohexylcarbodiimide (DCC) (4.54 grams, 22.0 mmoles, 1.10 equivalents) processing, the white suspension of generation is stirred overnight at room temperature under argon gas.Remove pyridine under the vacuum, then with benzene (2 * 15 milliliters) azeotropic.Residue oily matter is dissolved in ethyl acetate, filters, and with 1.0 equivalent hydrochloric acid and salt water washing, behind anhydrous sodium sulfate drying, vacuum-evaporation obtains the crude product of 8.272 gram title esters, for containing the sedimentary oily matter of a small amount of dicyclohexylurea (DCU) (DCU).TLC(7: 2: 1) Virahol-ammonium hydroxide-water.R f=0.60, ultraviolet and phospho-molybdic acid (PMA).
(7) (S)-3-(((1-dimethyl ethyl) quadrosilan base)-oxygen)-4-(chlorine methoxyl group phosphinyl)-butyric acid, methyl esters
F(6) Bu Fen phosphonic acids mono-methyl (6.595 grams, about 14.7 mmoles) be dissolved in exsiccant methylene dichloride (30 milliliters) with (5.60 milliliters of the trimethyl silyl diethylamine that heavily steams, 29.4 mmole, 2.0 equivalents) handle, stirring at room is 1 hour under argon gas.The mixture vaporising under vacuum, drive and vacuum-drying with benzene (1 * 30 milliliter), the light yellow thickness oily matter that obtains is dissolved in exsiccant methylene dichloride (30 milliliters) and dimethyl formamide (through 4 Molecular sieve drying, 2) in, limpid solution is cooled to-10 ℃ (salt/ice bath), drips the oxalyl chloride (1.41 milliliters, 16.2 mmoles, 1.1 equivalents) that heavily steams with syringe.Violent evolving gas, solution becomes deep yellow.Mixture stirred 15 minutes at-10 ℃ under argon gas, and then stirring at room is 1 hour.The mixture vaporising under vacuum, with benzene (1 * 30 milliliter) drive and vacuum-drying obtain the phosphonyl chloride crude product, be yellow oil.
G.(S)-4-((2-(4 '-fluoro-3,3 ', the 5-trimethylammonium-(1,1 '-biphenyl)-the 2-yl) ethynyl) the methoxyl group phosphinyl)-uncle's 3-fourth phenylbenzene siloxy-butyric acid, methyl esters
The acetylide of E part (2.678 grams, 11.2 dry tetrahydrofuran mmole) (20 milliliters) solution, drip (7 milliliters of the hexane solutions of 1.6M n-Butyl Lithium-78 ℃ (dry ice/acetone), 11.2 mmole, 1.0 equivalent), the red-purple mixture is under argon gas, stirred 1 hour at-78 ℃, rough heat is to 0 ℃, be cooled to-78 ℃ again, transfer in the dropping funnel and be added drop-wise in dry tetrahydrofuran (20 milliliters) solution of phosphonyl chloride (8.27 grams, 18.4 mmoles, 1.6 equivalents) of-78 ℃ (dry ice/acetone) F part with intubate.At-78 ℃ after 1 hour, mixture saturated ammonium chloride termination reaction then is warming to room temperature, uses ether extraction, and ether layer use anhydrous magnesium sulfate drying with saturated sodium bicarbonate and salt water washing, and evaporation obtains 11.705 and restrains brown oil.Thick oil is with flash chromatography method purifying on silica gel, with (7: 3) hexane-ethyl acetate washing.Merge the product part, evaporation obtains the acetylene phosphinate of 4.246 gram (56%) titles, is light brown oily matter.In addition, reclaim the biphenyl acetylene of 457 milligrams of (correcting yield 68%) E parts.TLC(7: 3) hexane-acetone, R f=0.20, ultraviolet and phospho-molybdic acid (PMA).
H.(S)-4-((2-(4 '-fluoro-3,3 ', the 5-trimethylammonium-(1,1 '-biphenyl)-the 2-yl) ethyl) the methoxyl group phosphinyl)-3-tert-butyl diphenyl siloxy-butyric acid, methyl esters
Methyl alcohol (5 milliliters) solution of the acetylene phosphinate (333 milligrams) of the C part of blowing with argon gas is handled with 10% palladium/carbon (121 milligrams, weight ratio 36%), leads to hydrogen (40psi) and swayed 30 hours on the Parr device.Remove catalyzer by the diatomite filtration of filling, after the filtrate evaporation, obtain light yellow oil.Thick oily matter is with flash chromatography method purifying on silica gel, with (1: 1) ethyl acetate-hexane wash-out.Obtain 250 milligrams of saturated phosphinates of (75%) title after the product evaporation, be limpid oily matter.TLC(4: 1) ethyl acetate-hexane, R f=0.33, ultraviolet and phospho-molybdic acid (PMA).
J.(S)-4-((2-(4 '-fluoro-3,3 ', the 5-trimethylammonium-(1,1 '-biphenyl)-the 2-yl) ethyl) the methoxyl group phosphinyl)-3-hydroxyl base butyric acid, methyl esters
(330 milligrams in the silicon ether of H part, 0.489 dry tetrahydrofuran mmole) (6 milliliters) solution, earlier with Glacial acetic acid (115 microlitres, 1.96 mmole, 4.0 equivalent), use again the 1.0M tetrabutylammonium fluoride tetrahydrofuran (THF) (1.47 milliliters, 1.47 mmoles, 3.0 solution-treated equivalent), the mixture of generation is stirred overnight at room temperature under argon gas.Mixture dilutes with 10 milliliters of frozen water, with ethyl acetate extraction (2 times).Organic phase is used anhydrous sodium sulfate drying with saturated sodium bicarbonate and salt water washing, obtains 364 milligrams of light yellow oil after the evaporation, and thick oily matter is with flash chromatography method purifying on silica gel, with (6: 4) acetone-hexane wash-out.Evaporate obtains partly that (205 milligrams of (96%) title free alcohol are limpid oily matter, slow crystallization when leaving standstill.TLC(7: 3) acetone-hexane, Rf=0.28, ultraviolet and phospho-molybdic acid (PMA).
Embodiment 2
(S)-4-((2-(4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)-the 2-yl) ethyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, di-potassium
The diester of embodiment 1 (187 milligrams, handle with the lithium hydroxide solution (1.29 milliliters, 1.29 mmoles, 3.0 equivalents) of 1.0N by 0.429 mmole) De diox (5 milliliters) solution.Mixture under argon gas in 55 ℃ of heating (oil bath) 2.5 hours.Reaction mixture, dilute with water filters vacuum-evaporation.Residuum is dissolved in the minimum water, goes up chromatography purification at HP-20 resin (25 millimeters of column diameters, thick about 15 centimetres of bed).The elder generation water, use (1: 1) methanol-water mixtures wash-out again.After the collection product partly evaporates, water-soluble (50 milliliters), the filter freezing drying obtains 175 milligrams of (91%, in hydrate weight) title dilithium salts, is white, static electrification solid.
TLC(8: 1: 1) methylene chloride-methanol-acetate, Rf=0.1, ultraviolet and phospho-molybdic acid (PMA), (7: 2: 1) Virahol-ammonium hydroxide-water, Rf=0.45, ultraviolet and phospho-molybdic acid (PMA).
C 21H 24O 5FPLi 2Ultimate analysis (molecular weight 450.90) with 1.7 mole of water
Calculated value: C, 55.93; H, 6.13; F, 4.21; P, 6.87
Measured value: C, 55.91; H, 5.84; F, 3.92; P, 6.89
1H-NMR（400MHz，CD 3OD
δ1.34-1.56ppm（4H，multiplet）
2.22-2.31ppm（2H，multiplet）
2.25+2.37ppm（6H，two singlets）
2.29ppm（3H，doublet，J H-F＝1.4Hz）
2.75ppm（2H，multiplet）
4.13ppm（1H，multiplet）
6.73-7.10ppm（5H，multiplet）
Embodiment 3
(S)-4-((2-(4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)-the 2-yl) ethynyl) the methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl esters
With (455 milligrams in embodiment 1G silicon ether partly, 0.678 mmole) and Glacial acetic acid (155 microlitres, 2.71 mmole, 4.0 the mixture in exsiccant tetrahydrofuran (THF) (7 milliliters) equivalent), with (2.0 milliliters of the tetrahydrofuran (THF)s of 1.0M tetrabutylammonium fluoride, 2.0 mmole, 3.0 equivalents) solution-treated, the solution of generation is stirred overnight at room temperature under argon gas.In the mixture impouring frozen water (10 milliliters), with ethyl acetate extraction (2 times).Organic phase is used anhydrous sodium sulfate drying with saturated sodium bicarbonate and salt water washing, and evaporation obtains 498 milligrams of yellow oil.Crude product with (3: 2) hexane-acetone wash-out, obtains 217 milligram (74%) title alcohol after the product evaporation with flash chromatography method purifying on silica gel, is colorless oil.
TLC(7: 3) hexane-acetone, Rf=0.10, ultraviolet and phospho-molybdic acid (PMA).
Embodiment 4
(S)-4-((2-(4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)-the 2-yl) ethynyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
The diester of embodiment 3 (203 milligrams, the mixture in the 0.469 mmole) Zai diox (6 milliliters) is handled with 1.0N lithium hydroxide (1.6 milliliters, 1.6 mmoles, 3.5 equivalents), solution under argon gas 55 ℃ of heating (oil bath) 30 minutes.Cooling, dilute with water filters, evaporation back (30 milliliters) soluble in water, and lyophilize.The white lyophilized products is dissolved in the minimal amount of water, goes up chromatography purification at HP-20 resin (25 millimeters of column diameters, thick 10 centimetres of resin bed), and first water is used (50: 50) water-methanol wash-out again.Merge the product part, evaporation, residuum (30 milliliters) soluble in water, and lyophilize obtain 199 milligrams of (97%, in hydrate, molecular weight=435.36) title dilithium salts, are white solid.
TLC(8: 1: 1) methylene chloride-methanol-acetate, Rf=0.13, ultraviolet and phospho-molybdic acid (PMA)
C 21H 20O 5FPLi 2The ultimate analysis of+1.06 mole of water (molecular weight 435.36):
Calculated value: C, 57.93; H, 5.12; F, 4.36; P, 7.11
Measured value: C, 57.91; H, 4.89; F, 4.22; P.6.89
1H NMR（400MHzCD 3OD）：
δ1.76-1.82ppm（2H，multiplet）
2.32（3H，doublet，J HF＝1.8Hz）
2.34（3H，singlet）
2.37（1H，dd，J＝8.4Hz）
2.41（1H，dd，J＝4.1Hz）
2.49（3H，singlet）
4.27（1H，multiplet）
6.98-7.37（5H，m）
Embodiment 5
(S, Z)-4-((2-(4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)-the 2-yl) vinyl) the methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl esters
A.(S, Z)-4-((2-(4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)-the 2-yl) vinyl)-the methoxyl group phosphinyl)-3-tert-butyl diphenyl siloxy--butyric acid, methyl esters
Methyl alcohol (10 milliliters) the solution degassing back of embodiment 1G acetylene phosphinate (498 milligrams, 0.742 mmole) is partly handled with 10% palladium/carbon (50 milligrams, weight ratio 10%).Black suspension stirred 2 hours down at logical hydrogen (1 normal atmosphere).Remove catalyzer by diatomite filtration, obtain 500 milligrams of yellow oil after the filtrate evaporation.Crude product is with flash chromatography method purifying on silica gel, with (3: 2) hexane-eluent ethyl acetate.The merging product partly evaporates and obtains 498 milligrams of (100%) desired olefin(e) compounds, is colorless oil.
TLC(4: 1) ethyl acetate-hexane, diastereomer Rf=0.44 and 0.51, ultraviolet and phospho-molybdic acid (PMA)
B.(S, Z)-4-((2-(4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)-the 2-yl) vinyl)-the methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl esters
Dry tetrahydrofuran (6 milliliters) solution of the silicon ether (498 milligrams, 0.74 mmole) of A part is earlier with Glacial acetic acid (170 microlitres, 2.96 mmoles, 4.0 equivalent) handle, use tetrahydrofuran (THF) (2.2 milliliters, 2.2 mmoles, the 3.0 equivalents) solution-treated of 1.0M tetrabutylammonium fluoride again.This limpid, colourless mixture stirring at room 16 hours under argon gas.TLC shows still remaining a spot of starting raw material.Add acetic acid (40 microlitres, 1.0 equivalents) again and fluoridize four positive fourth ammoniums (0.74 milliliter, 1.0 equivalents), continue to stir 6 hours.Mixture is with frozen water (10 milliliters) dilution, with ethyl acetate extraction (2 times).United extraction liquid with saturated sodium bicarbonate and salt water washing, is used anhydrous sodium sulfate drying, and evaporation obtains 468 milligrams of light yellow oil.Crude product is with flash chromatography method purifying on silica gel, with (7: 3) hexane-acetone wash-out.Merge product and evaporation, obtain 243 milligrams of (76%) title alcohol, be colorless oil.
TLC(7: 3) hexane-acetone, Rf=0.19, ultraviolet and phospho-molybdic acid (PMA)
Embodiment 6
(S, Z)-4-((2-(4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)-the 2-yl) vinyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
The diester of embodiment 5 (240 milligrams, 0.552 mmole) De diox (7 milliliters) solution, with 1.0N lithium hydroxide (1.9 milliliters, 1.9 mmoles, 3.5 equivalents) solution-treated, with this mixture under argon gas, 50 ℃ of heated and stirred (oil bath) 3 hours.Obvious white precipitate appears.Cooling mixture, dilute with water filters and vacuum-evaporation, obtains white solid.This crude product is dissolved in the minimum water, and at the enterprising circumstances in which people get things ready for a trip spectrum of HP-20 resin purifying, first water is then used (50: 50) water: methanol-eluted fractions.Merge the product part, (50 milliliters) soluble in water again after the evaporation filter and lyophilize, obtain the title dilithium salt of 255 milligrams (100%, in hydrate, molecular weight 457.58), are the solid of white, static electrification.
TLC(8: 1: 1) methylene chloride-methanol-acetate, Rf=0.26, ultraviolet and phospho-molybdic acid (PMA)
C 21H 22O 5FPLi 2The ultimate analysis of+2.18 mole of water (457.58):
Calculated value: C, 55.12; H, 5.81; F, 4.15; P, 6.77
Measured value: C, 55.35; H, 5.68; F.4.27; P, 7.09
1H NMR（400MHz，CD 3OD）：
δ1.24ppm（2H，multiplet）
2.09（2H，doublet，J＝6.2Hz）
2.27（3H，doublet，J HF＝1.8Hz）
2.30（3H，singlet）
2.38（3H，singlet）
4.06（1H，multiplet）
5.87（1H，d doublet，J HH＝12，4Hz，
J HP＝14.3Hz）
6.87（1H，s）
6.91（1H，d doublet，J HP＝43.4Hz）
6.98（2H，triplet）
7.22（2H，multiplet）
Embodiment 7
(S)-and 4-((2-(3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indoles-2-yl) ethyl) the methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl esters
A.2-((4-fluorophenyl) methyl)-3-ketobutyric acid, ethyl ester
Stir down with sodium sheet (8.31 grams, 362 mmoles) be dissolved in the dehydrated alcohol (1 liter), the methyl aceto acetate that will heavily steam under argon gas (47 grams, 362 mmoles, 1 equivalent) is added in this clear solution, after this pale yellow mixture refluxed 1 hour, be cooled to room temperature, with 4-fluoro benzyl bromide (75 grams, 398 mmoles, 1.1 equivalent) handle this light orange mixture stirring at room 2.5 hours under argon gas.Vacuum concentration, residuum distributes between ethyl acetate-water, and anhydrous sodium sulfate drying is used in organic phase water (2 times) and salt water washing, and evaporation obtains orange.This crude product of vacuum distilling purifying (5 mmhg) obtains 46.47 gram (54%) alkylates, is limpid colourless liquid, 142 °-144 ℃ of boiling points.
TLC(7: 3) hexane-ether, product Rf=0.31
1H NMR（CDCl 3）：δ1.20（3H，t），2.19（3H，s），3.13（2H，d），3.73（1H，t），4.14（2H，q），6.95（2H，t），7.13（2H，m）ppm.
13C NMR（CD 3CN）：δ14.4，29.7，33.7，62.1，62.3，115.3，116.8，131.4，131.9，145.1（J C-F＝284Hz），170.1，203.5ppm.
B.3-(4-fluorophenyl)-the 1H-Ethyl indole-2-carboxylate
With reference to chemical abstracts Vol, 33, P587
With reference to J.Chem.Society such as Helmuth R.
PP.6-7（1927）
With reference to Preparativc Organic Chcmistvy 4th Ed.
P.582（1972）
The ester of A part (46.4 grams, 195 mmoles) dehydrated alcohol (290 milliliters) solution, handle with aqueous sodium hydroxide solution (23.4 grams are dissolved in 58 ml waters) earlier at 0 ℃ (ice bath), use the diazonium chloride benzole soln (with reference to Prep.Org.Chem. more immediately, the 4th edition is P.582(1972) make by aniline (17.8 milliliters), concentrated hydrochloric acid (88 milliliters), water (98 milliliters) and Sodium Nitrite (13.5 gram)) handle, dark orange red two phase liquid obtained.This mixture is stirring at room 1 hour, in the impouring frozen water (500 milliliters), with ethyl acetate extraction (3 * 300 milliliters).Organic phase is used anhydrous sodium sulfate drying with salt water washing (500 milliliters), and vacuum-evaporation obtains the crude product of 55.62 gram hydrazone intermediates, is orange.TLC(7: 3) hexane-ether, the Rf=0.22 of hydrazone, ultraviolet and phospho-molybdic acid (PMA), the hydrazone crude product is used to proceed the Fischer cyclization.
The dehydrated alcohol of hydrazone (200 milliliters) solution, bubbling ventilation attitude hydrogenchloride 30 minutes is interrupted with ice bath simultaneously and cools off.In this browny mixture impouring frozen water (600 milliliters), with ethyl acetate extraction (3 times).Anhydrous sodium sulfate drying is used in organic phase water (2 times) and salt water washing, and vacuum-evaporation obtains the brown solid.Grind with ice-cold hexane, filter, obtain the title indoles thing of 26.74 gram (49%) expections, be the tawny granular crystal, fusing point 129-130 ℃.
TLC(7: 3) hexane-acetate, Rf=0.26, ultraviolet and phospho-molybdic acid (PMA)
C 17H 14FNO 2Ultimate analysis
Calculated value: C, 72.07; H, 4.98; F, 6.71; N, 4.94
Measured value: C, 72.38; H, 5.05; F, 6.87; N, 5.01
1H NMR（CDCl 3）：δ1.22ppm（3H，t），4.29（2H，q），7.10-7.62（8H，m），9.21（1H，bs）ppm.
13C NMR（CDCl 3）：δ14.1，60.9，111.8，114.5，114.8，120.9，121.4，122.9，123.1，125.9，127.9，129.5，132.2（J C-F＝7.6Hz），135.7，162.0，162.2（J C-F＝244Hz）ppm.
C.3-(4-fluorophenyl)-the 1-(1-methylethyl)-the 1H-Indoline-2-carboxylic acid, ethyl ester
With reference to the Sandoz international monopoly *158675 P.35(1984)
The indoles of B part (26.74 grams, 94.4 mmole) be dissolved in the dry N,N-DIMETHYLACETAMIDE (100 milliliters) that heavily steams, this solution places under 0 ℃ (ice bath), adding in batches (violent evolving gas) is dispersed in 60% sodium hydride (4.53 grams in the mineral oil, 113.3 mmole, 1.2 equivalent) handle, mixture is under argon gas, 0 ℃ of stirring 1 hour.Add 2-iodopropane (85 grams, 500 mmoles, 5.3 equivalents), mixture is warming to room temperature and stirred 1 hour under argon gas, be cooled to 0 ℃ again, again with other 1.2 normal sodium hydrides processing, stirring at room 1 hour.Repeat this step twice again.Last mixture is cooled to 0 ℃ (ice bath), carefully drips dehydrated alcohol (30 milliliters) and makes excessive sodium hydride termination reaction.Mixture dilutes with ethyl acetate, and with the washing of 5% sal enixum, water extracts once with ethyl acetate is anti-, the combined ethyl acetate layer, and anhydrous sodium sulfate drying is used in water and salt solution (2 times) washing, and evaporation obtains 38.54 gram brown solid.This solid is dissolved in the hot methylene dichloride, adds hexane initial indoles is crystallized out.Reclaim the initial indoles of 13.88 grams.The vacuum-evaporation mother liquor obtains 22.32 gram brown oil.Crude product is used hexane earlier with flash chromatography method purifying on silica gel, uses (95: 5) hexane-acetone wash-out again.Evaporate partly obtains the N-isopropyl indole of 6.55 gram (21%) (correcting yield 62%) titles, is yellow oil.
TLC(4: 1) hexane-acetone, Rf=0.57, ultraviolet and phospho-molybdic acid (PMA)
1H NMR（CDCl 3）：δ1.04（3H，t），1.20（6H，d），4.17（2H，q），5.40（1H，m），7.10-7.7（8H，m）ppm.
13C NMR（CDCl 3）：δ13.6，21.5，48.7，53.3，60.8，112.7，114.5，114.8，120.3，121.4，122.4，124.3，125.9，127.6，130.8，131.7（J C-F＝7.5Hz），136.2，162.3（J C-F＝144Hz），163.0ppm.
D.3-(4-fluorophenyl)-the 1-(1-methylethyl)-1H-indoles-2-methyl alcohol
Lithium aluminum hydride (1.12 grams, 29.6 mmoles, 1.5 equivalents) is carefully joined in the ether (30 milliliters) of the drying of 0 ℃ (ice bath), heavily steaming.The suspension that obtains was added dropwise to the diethyl ether solution of the K-281 (6.42 grams, 19.7 mmoles are dissolved in 20 milliliters of ether) of C part and handles in 10 minutes.At 0 ℃, under argon gas, stir after 30 minutes, drip water (1.1 milliliters) successively, 15% sodium hydroxide (1.1 milliliters) and water (3.4 milliliters) make the mixture termination reaction, the suspension that produces filters by the bed of diatomaceous earth of filling, use anhydrous magnesium sulfate drying, vacuum-evaporation obtains the yellow foam thing of 5.1 grams.Crude product with (85: 15) hexane-acetone wash-out, obtains 5.08 gram (91%) purified title alcohol with flash chromatography method purifying on silica gel, is the weak yellow foam thing.
TLC(7: 3) hexane-acetone, Rf=0.38, ultraviolet and phospho-molybdic acid (PMA), small amount of sample crystallizes out from hexane, obtains white crystals shape title alcohol, fusing point 101-103 ℃
Ultimate analysis C 18H 17NOF:
Calculated value: C, 76.30; H, 6.40; F, 6.71; N, 4.94
Measured value: C, 76.49; H, 6.46; F, 6.84; N, 4.88
1H NMR（CDCl 3）：δ1.60（1H，t），1.69（6H，d），4.76（2H，d），4.93（1H，m），7.05-7.62（8H，m）ppm.
13C NMR（CDCl 3）：δ20.9，47.3，54.8，113.0，115.9，116.3，116.6，120.2，120.6，122.9，128.5，131.6，132.4，135.1，135.7，163.0（J C-F＝245Hz）ppm.
E.3-(4-fluorophenyl)-the 1-(1-methylethyl)-1H-indoles-2-formaldehyde
Dry methylene chloride (30 milliliters) solution of Dess-Martin periodo alkane (5.9 grams, 13.9 mmoles, 1.2 equivalents) is handled with the exsiccant trimethyl carbinol (1.3 milliliters, 13.9 mmoles, 1.2 equivalents).Mixture stirring at room 15 minutes under argon gas.The indanol (3.28 grams, 11.6 mmoles, 1 equivalent) that will be dissolved in the D part in the exsiccant methylene dichloride (12 milliliters) was added dropwise to wherein at 5 minutes, yellow mixture stirring at room 1 hour under argon gas.Reaction mixture is added to Sulfothiorine (15.3 grams that stirring, 97 mmoles, 7 equivalents) be dissolved in the solution of 1.0N sodium pyrosulfate (40 milliliters) of new preparation, the mixture that vigorous stirring produces 5 minutes, isolate organic phase, with 1.0N sodium bicarbonate, water and salt water washing, use anhydrous sodium sulfate drying, evaporation obtains 3.69 gram yellow oil.Crude product with (40: 1) hexane-ether wash-out, obtains 2.7 gram (83%) purified title aldehyde with flash chromatography method purifying on silica gel, is white crystalline solid, fusing point 88-89 ℃
TLC(7: 3) hexane-acetone, Rf=0.56, ultraviolet and phospho-molybdic acid (PMA)
Ultimate analysis C 18H 16FNO:
Calculated value: C, 76.85; H, 5.73; N, 4.98; F.6.75
Measured value: C, 76.91; H, 5.71; N, 4.95; F, 6.76
1H NMR（CDCl 3）：δ1.69（6H，d），5.92（1H，m），7.10-7.70（8H，m），9.80（1H，s）ppm.
13C NMR（CDCl 3）：δ21.4，48.0，112.5，113.2，115.4，115.7，120.8，122.1，126.9，127.0，132.0，132.6（J C-F＝7.5Hz），183.6ppm.
F.3-(4-fluorophenyl)-the 1-(1-methylethyl)-2-(2, the 2-dibromo vinyl)-the 1H-indoles
In (15 ℃ of refrigerative, ice/salt bath) indolal of E part (1.84 grams, 6.54 mmole) and triphenyl (5.14 the gram, 19.6 mmole, 3 equivalents) in dry methylene chloride (30 milliliters) solution, in 5 minutes, splash into carbon tetrabromide (3.25 grams, 9.8 mmoles, 1.5 dry methylene chloride equivalent) (10 milliliters) solution, yellow mixture stirred 15 minutes under 15 ℃ of argon gas.Mixture distributes between saturated sodium bicarbonate and methylene dichloride, and organic phase is used anhydrous sodium sulfate drying with saturated sodium bicarbonate and salt water washing, and evaporation obtains 9.44 gram brown oil.Crude product is with flash chromatography method purifying on silica gel, with (95: 5) hexane-methylene dichloride wash-out.Evaporate partly obtains 2.87 gram (100%) title vinyl dibromide, is yellow oil.Leave standstill crystallization.With the ether recrystallization once obtain 2.46 the gram (86%) purifying product, be light yellow granular crystal, fusing point 135-137 ℃.
TLC(7: 3) hexane-methylene dichloride, Rf=0.45, ultraviolet and phospho-molybdic acid (PMA)
Ultimate analysis C 19H 16NFBr 2:
Calculated value: C, 52.20; H, 3.69; N, 3.20; Br, 36.56
Measured value: C, 52.25; H, 3.68; N, 3.20; Br, 36.58
1H NMR（CDCl 3）：δ1.15（6H，d），4.67（1H，m），7.10-7.70（9H，m）ppm.
13C NMR（CDCl 3）：δ21.9，48.6，98.6，111.6，115.3，115.6，115.9，119.9（J C-F＝7.6Hz），122.4，127.5，129.3，130.5，130.7，130.9，135.2，161.5（J C-F＝246Hz）ppm.
G.3-(4-fluorophenyl)-the 1-(1-methylethyl)-2-ethynyl-1H-indoles
Vinyl dibromide (2.395 grams in the F of-78 ℃ (dry ice/acetone) part, 5.48 in dry tetrahydrofuran mmole) (10 milliliters) solution, under argon gas, drip (6.9 milliliters of n-Butyl Lithium-hexane solutions of 1.6M, 10.96 mmole, 2 equivalents), the mixture that produces stirred 1 hour at-78 ℃, dripped saturated ammonium chloride (5 milliliters) then and made reaction terminating.Mixture is used twice of ether extraction after being warmed to room temperature.Anhydrous magnesium sulfate drying is used in the salt water washing of ether layer, and vacuum-evaporation obtains dun oily matter 1.893 grams.Crude product is gone up purifying with the flash chromatography method at silica gel (80: 1), with (200: 1) hexane-ether wash-out, obtain 1.12 gram purified products, be the acetylene thing of (3.3: 1) and the mixture of end alkene thing, mixture is in aluminum oxide (neutrality, activity=II) the enterprising circumstances in which people get things ready for a trip spectrum of post is separated, with (200: 1) hexane-ether wash-out.Evaporate partly obtains 900 milligrams of canescence crystal.With hot hexane recrystallization once, obtain the title acetylene thing of 700 milligrams of (46%) purifying, be the white needles thing, fusing point 105-106 ℃.TLC(95: 5) hexane-ether, the Rf=0.44 of acetylene thing, the Rf=0.49 of alkene thing, ultraviolet and phospho-molybdic acid (PMA)
Ultimate analysis C 19H 16NF:
Calculated value: C, 82.28; H, 5.81; N, 5.05; F, 6.85
Measured value: C, 82.70; H, 5.85; N, 5.10; F, 6.62
1H NMR（CDCl 3）：δ1.70（6H，d），3.5（1H，s），5.06（1H，m），7.10-7.75（8H，m）ppm.
H.(S)-4-((2-(3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indoles-2-yl) ethynyl)-the methoxyl group phosphinyl)-3-(tert-butyl diphenyl siloxy-) butyric acid, methyl esters
In (678 milligrams of the G of-78 ℃ (dry ice/acetone) acetylene things partly, 244 mmoles, 1.0 equivalents) in dry tetrahydrofuran (6 milliliters) solution, under argon gas, splash into (1.53 milliliters of the hexane solutions of 1.6M n-Butyl Lithium, 2.44 mmole, 1.0 equivalents).At-78 ℃ after 30 minutes, this mixture moved on to intubate in-78 ℃ dry tetrahydrofuran (5 milliliters) solution of phosphonyl chloride (about 4.3 mmoles, 1.75 equivalents) of embodiment 1F part.The dun mixture stirred 30 minutes at-78 ℃, dripped saturated ammonium chloride (5 milliliters) termination reaction, was warmed to room temperature.Mixture with saturated ammonium chloride and salt water washing, is used anhydrous magnesium sulfate drying with ether extraction twice, and vacuum-evaporation obtains 2.567 gram red-brown oily matter.Thick oil with (3: 2) hexane-eluent ethyl acetate, obtains 756 milligrams of (44%) title acetylene phosphinates with flash chromatography method purifying on silica gel, is deep yellow oily thing.
TLC(7: 3) hexane-acetone, Rf=0.27 ultraviolet and phospho-molybdic acid (PMA)
1H NMR（CDCl 3）：δ1.0（9H，s），1.64（6H，d），2.10-2.90（4H，m），3.56（3H，s），3.58（3H，dd），4.6（1H，bm），4.90（1H，m），7.05-7.55（18H，m）ppm.
13C NMR（CDCl 3）：δ14.2，19.1，21.0，26.7，27.8，37.5，39.2，42.2，45.1，49.2，51.4，51.9，60.3，65.5（J C-P＝15.1Hz），88.1，91.2，98.3，111.3，115.3，115.6，120.8（J＝5.7Hz），122.3，124.9，125.9，126.4，127.6，129.2，130.7，133.0，135.7，136.1，170.9ppm.
J.(S)-and 4-((2-(3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indoles-2-yl) ethyl) the methoxyl group phosphinyl)-3-tert-butyl diphenyl siloxy-) butyric acid, methyl esters
With methyl alcohol (9 milliliters) solution of the H part acetylene phosphinate (422 milligrams) of argon gas purge, handle with 10% platinum/carbon (420 milligrams).The mixture that obtains logical (40PSi) hydrogen on the Parr device swayed 2 hours.Remove catalyzer by diatomite filtration, obtain the indoles phosphinate of 380 milligrams of (90%) titles after the filtrate evaporation, be yellow foam thing,
TLC(4: 1) ethyl acetate-hexane, Rf=0.27, ultraviolet and phospho-molybdic acid (PMA)
1H NMR（CDCl 3）：δ1.00（9H，s），1.63（6H，d），1.5-2.0（2H，m），2.20（1H，m），2.58-3.00（5H，m），3.44（3H，dd，J H-P＝10.6Hz），3.61（3H，s），4.52（2H，m），7.07-7.66（18H，m）ppm.
13C NMR（CDCl 3）：δ12.6，16.8，17.2，19.1，21.5，26.7，36.0，42.1，47.2，50.9，51.4，65.8;111.8，115.3，119.1，121.1，127.7，128.3，129.9，131.2，131.3，132.8，133.4，134.3，134.8，135.7，171.3ppm.
K.(S)-and 4-((2-(3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indoles-2-yl) ethyl) the methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl esters
(379 milligrams in J part silicon ether, 0.531 dry tetrahydrofuran mmole) (5 milliliters) solution, use Glacial acetic acid (120 microlitres successively, 2.12 mmole, 4 equivalents) and (1.6 milliliters of the tetrahydrofuran solutions of 1.0M tetrabutylammonium fluoride, 1.6 mmole, 3 equivalents) to handle, the solution of generation is stirred overnight at room temperature under argon gas.Mixture is used ethyl acetate extraction twice with frozen water (10 milliliters) dilution, organic phase saturated sodium bicarbonate and salt water washing, use anhydrous sodium sulfate drying, evaporation obtains 408 milligrams of yellow oil, and crude product is with flash chromatography method purifying on silica gel, with (7: 3) acetone-hexane wash-out.Evaporate partly obtains the title alcohol of 197 milligrams (78%), is the white foam thing.
TLC(1: 1) hexane-acetone, Rf=0.09 ultraviolet and phospho-molybdic acid (PMA)
1H NMR（CDCl 3）：δ1.68（6H，d），1.80-2.0（2H，m），2.10（2H，m），2.58（2H，m），3.08（2H，m），3.63（3H，dd，J H-P＝10.1Hz），3.70（3H，d），3.96（1H，t），4.35+4.49（1H，2 broad multiplets），4.67（1H，m），7.0-7.6（8H，m）ppm.
13C NMR（CDCl 3）：δ17.6，17.7，21.4，29.2，29.4，33.2，33.3，34.6，41.6，41.8，42.0，42.2，47.3，50.9，51.7，63.4，111.8，113.5，115.2，115.5，119.0，119.4，121.1，128.3，131.3，131.5，134.2，134.8，161.5 J C-F＝244.1Hz），172.1ppm.
Embodiment 8
(S)-and 4-((2-(3-(4-fluorophenyl)-1-(1-aminomethyl phenyl)-1H-indoles-2-yl) ethyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
Stir embodiment 7 diester (197 milligrams, 0.414 mmole) De diox (5 milliliters) solution is handled with 1.0N lithium hydroxide (1.45 milliliters, 3.5 equivalents), the white suspension of generation under argon gas 55 ℃ of heating (oil bath) 40 minutes.Cooling mixture, dilute with water filters vacuum-evaporation.Residuum is dissolved in the minimal amount of water, separates first water, back (50: 50) water-methanol wash-out in the enterprising circumstances in which people get things ready for a trip spectrum of HP-20 resin.Merge the product part, and evaporation.In the glass residuum water-soluble (50 milliliters), filtration and lyophilize obtain 178 milligrams (85% in hydrate) purified title dilithium salt, are white solid.
Ultimate analysis C 23H 25The NFP2Li+2.52 mole; H 2O
（MW 504.71）：
Calculated value: C, 54.73; H, 6.00; N, 2.78; F, 3.76; P, 6.14
Measured value: C, 54.62; H, 5.67; N, 2.90; F, 3.61; P, 6.06
1H NMR（400MHz，CDCl 3）：
δ 1.69ppm（6H，dd，J＝5.8Hz）
1.71（2H，multiplet）
1.93（2H，multiplet）
2.38（2H，multiplet）
3.06（2H，quartet）
4.32（1H，multiplet）
4.87（1H，multiplet）
6.97（1H，dt，J＝0.7Hz）
7.07（1H，dt，J＝1.1Hz）
7.16（2H，t）
7.41（3H，m）
7.57（1H，1/2 AB quartet）
Embodiment 9
(S)-4-((2-((1,1 '-biphenyl)-the 2-yl) ethyl) the methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl esters
A. biphenyl-2-formaldehyde
Dess-Martin periodo alkane (27.64 grams, 65.2 mmoles) stirs with 150 milliliters of methylene dichloride under argon gas.The exsiccant trimethyl carbinol (8.0 milliliters) joins in the solution that is stirring.Mixture is stirring at room 10 minutes, with 15 minutes in methylene dichloride (20 milliliters) solution that wherein splashes into biphenyl-2-methyl alcohol (10 grams, 54.3 mmoles), splash into afterreaction and can at room temperature stir and carry out.After the stirring at room 1 hour, add 600 milliliters of anhydrous diethyl ethers, add 1N sodium hydroxide (225 milliliters) again.After 10 minutes, filter the soup compound that produces, filter cake washs with ether.Filtrate is washed twice with 250 milliliters of 1N sodium hydroxide.The organic phase dried over mgso is filtered and is removed and obtains yellow oil (10 gram) after desolvating.Through flash chromatography method purifying (silica gel, 1: 10/ ether: obtain title aldehyde (9.58 grams, 97%) hexane), be colorless oil.The TLC(1/9 ethyl acetate/hexane, silica gel) R f=0.29
The IR(film) 3065,3025,2850,2760,1685,1700,1600,1470,1450,1395cm -1
1H NMR（270MHz）（CDCl 3）
δ8.00（d，1，J＝70.Hz），7.60（m，1），7.40（m，7）.
Mass Spec m/e 183（M ++H）.
B.2-(2,2-dibromo vinyl)-(1,1 '-biphenyl)
Methylene dichloride (60 milliliters) solution of A aldehyde (2.0 grams, 11 mmoles) partly is cooled to-10 ℃ under argon gas.Add triphenylphosphine (9.21 grams, 35 mmoles), stir this mixture and all dissolve up to solid.With methylene dichloride (40 milliliters) solution of carbon tetrabromide (5.5 gram, 16.5 mmoles),, be added in the solution of above generation in 15 minutes at-10 ℃.Be reflected at-10 ℃, stirred 1 hour 15 minutes, then, add 50 milliliters of saturated sodium bicarbonate aqueous solution termination reactions at-10 ℃.Separate dichloromethane and water layer, water layer more once with dichloromethane extraction, the combined dichloromethane extracting solution, with each washing of saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution once.The dichloromethane extract dried over sodium sulfate is evaporated to dried.Crude product is used the hexane wash-out with flash chromatography method purifying, obtains the title dibromide, is pale solid (2.45 grams, 66%).
TLC(5: 95/ ethyl acetate: hexane, silica gel), R f=0.47
IR（CHCl 3）3064，3011，1596，1473，1450，1435，889，860，702cm -1
1H NMR（270MHz）（CDCl 3）
δ7.75（m，l），7.35（m，8），7.20（s，1）
13C NMR（67.0MHz）（CDCl 3）
δ141.06，140.08，137.49，133.83，129.81，129.45，129.17，128.61，128.22，127.50，127.08，90.78
Mass Spec m/e 337/339/341（M ++H）
C.2-ethynyl-(1,1 '-biphenyl)
Tetrahydrofuran (THF) (35 milliliters) solution of the vinyl dibromide of B part (2.31 grams, 6.9 mmoles) is cooled to-78 ℃ under argon gas.-78 ℃ while stirring in 10 minutes in wherein adding n-Butyl Lithium (5.52 milliliters, the hexane solution of 2.5M).After adding n-Butyl Lithium, reaction mixture becomes amaranth.After 2 hours 45 minutes, use the saturated aqueous ammonium chloride termination reaction-78 ℃ of stirrings.Be warmed to room temperature behind the reaction terminating, remove tetrahydrofuran (THF), the residuum dilute with water extracts three times with ether/hexane.The organic extraction dried over mgso is filtered and is obtained 1.3 gram yellow oil.With flash chromatography method purifying,, obtain title acetylene compound (1.04 grams, 88%) with 1% ether/hexane wash-out
The TLC(100% hexane, silica gel) R f=0.16
The IR(film) 3287,3061,3026,1474,1449,1432,1008,775,758,738cm -1
1H NMR（270MHz）
（CDCl 3）δ7.68（m，3），7.35（m，6），3.00（s，1）
13C NMR（67.8MHz）（CDCl 3）
δ144.40，140.22，133.83，129.56，129.20;128.92，127.95，127.49，126.94，120.44，83.08，80.15
Mass Spec m/e 179（M ++H）.
D.(S)-4-((2-((1,1 '-biphenyl)-the 2-yl)-ethynyl) the methoxyl group phosphinyl)-3-(tert-butyl diphenyl siloxy-) butyric acid, methyl esters
The acetylene compound of C part (0.332 gram, 1.86 mmoles) is added in 10 milliliters of tetrahydrofuran (THF)s, under argon gas ,-78 ℃ of stirrings.Toward wherein adding n-Butyl Lithium (0.75 milliliter 2.5M hexane solution) in 5 minutes.Reaction mixture stirred 1 hour at-78 ℃, was warmed to room temperature again, stirred 10 minutes, heavily was cooled to-78 ℃ again.The acetylene anion solutions was added drop-wise in 8 minutes in the phosphonyl chloride (2.98 mmole) and 10 milliliters of tetrahydrofuran solutions (under argon gas, being cooled to-78 ℃) of 10 milliliters of embodiment 1F parts.Dropwise, reactant stirred 1 hour at-78 ℃, added the saturated aqueous ammonium chloride termination reaction then.Be warmed to room temperature again,, use ether extraction three times with half saturated sodium chloride aqueous solution dilution.Merge ether extracted liquid, with saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing.Ether layer dried over mgso, evaporation obtain 1.5 gram yellow oil.With flash chromatography method purifying, with 5: 1: 4 hexane: toluene: eluent ethyl acetate obtains the acetylene phosphinate (0.543 gram, 48%) of title.
TLC(5: 1: 4 hexane: toluene: ethyl acetate, silica gel), R f=0.20
IR（CHCl 3）3070，3053，3035，3000，2952，2934，2896，2859，2178，1735，1474，1448，1436，1429cm -1
1H NMR（270MHz）CDCl 3）
δ7.65（m，3），7.65-7.28（m，16），4.55（m，1），3.55（d，3），3.40（dd，3），2.80（m，1），2.55（m，1），2.35（m，1），2.08（m，1），1.00（s，9）
13C（67.8Mz）（CDCl 3）
δ170.83，145.29，145.19，139.22，135.95，135.59，133.86，133.75，133.16，132.86，130.57，129.56，129.34，128.81，127.92，127.75，127.44，127.39，126.94，117.90，100.91，100.38，100.18，84.51，81.60，65.53，65.42，60.06，51.61，51.50，51.11，42.07，41.90，38.86，37.16，26.56，20.75，18.97，13.97
Mass Spec m/e 611（M ++H）
E.(S)-4-((2-((1,1 '-biphenyl)-the 2-yl) ethyl)-the methoxyl group phosphinyl)-3-(tert-butyl diphenyl siloxy-) butyric acid, methyl esters
The logical argon gas of bubbling is 10 minutes in methyl alcohol (8 milliliters) solution of the acetylene phosphinate of D part (0.515 gram, 0.85 mmole).(0.190 gram carries out Parr hydrogenation reaction (logical 43Psi hydrogen) to add 10% palladium/carbon.After swaying 25 hours under the 43Psi hydrogen, use the diatomite filtration methanol solution, evaporated filtrate obtains title phosphinate (0.510 gram, 98%), is colorless oil.
TLC(4: 1 ethyl acetate: R hexane) f=0.21
IR（CHCl 3）3071，3054，2998，2954，2934，2902，2859，1734，1477，1462，1448，1438，1428cm -1
1H NMR（270MHz）（CDCl 3）
δ7.65（m，3），7.55-7.00（m，16），4.45（m，1），3.58（s，3），3.30-3.20（2 doublets，3，J＝11Hz），2.88（m，1），2.60（m，3），2.17-1.80（m，1），1.80-1.30（m，1），1.00（s，3）
13C NMR（67.8MH）（Diagnostic peaks）（CDCl 3）
δ171.33，65.78，51.36，42.24，26.75
Mass Spec m/e 615（M ++H）
F.(S)-4-(2-((1,1 '-biphenyl)-the 2-yl) ethyl)-the methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl esters
Tetrahydrofuran (THF) (10 milliliters) solution of the phosphinate of E part (0.500 gram, 0.82 mmole) stirs together with acetate (0.19 milliliter, 3.3 mmoles) under argon gas, drips under the room temperature and fluoridizes four positive fourth ammoniums (2.45 milliliters, the 1.0M tetrahydrofuran solution).Reactant is in stirring at room after 23 hours, with 15 milliliters of frozen water termination reactions.Water layer ethyl acetate extraction three times.Merge organic solution, use the saturated sodium bicarbonate aqueous solution washed twice, once with the saturated sodium-chloride water solution washing.Organic layer dried over sodium sulfate, evaporation obtain 0.437 gram colorless oil.With flash chromatography method purifying, with 7: 3 acetone: the hexane wash-out, obtain title alcohol (0.247 gram, 81%), be colorless oil.
TLC(7: 3 acetone: hexane, silica gel) R f=0.22
IR（CHCl 3）3600-3171（br），3064，3009，2954，1731，1479，1439，1237，1180，1042，999cm -1
1H NMR（270MHz）（CDCl 3）
δ7.50-7.10（m，9），4.50-4.15（m，1），3.70（s，3），3.53 & 3.50（2 doublets，3，J＝11Hz），2.88（m，2），2.50（m，2），2.00-1.60（m，4）
13C NMR（67.8MHz）（CDCl 3）
δ171.55，171.49，141.39，141.00，138.10，137.88，129.95，128.81，128.06，127.53，26.83，126.22，63.08，63.02，62.85，51.39，50.58，50.47，42.35，42.15，42.07，41.87，34.31，33.06，33.00，30.77，30.52，29.49，29.21，25.41
Mass Spec m/e 377（M ++H）
Embodiment 10
(S)-4-(2-(1,1 '-biphenyl-2-yl) ethyl) hydroxyl oxygen phosphino--3-hydroxybutyric acid, dilithium salt
(0.239 gram stirs under argon gas in the 0.64 mmole) Zai diox (6.5 milliliters) with the diester of embodiment 9.Under the room temperature, add the lithium hydroxide solution of 1.9 milliliters of 1.0M.Stir this mixture down at 55 ℃.Stir after 2.5 hours, reactant is cooled to room temperature, and rotary evaporation is removed diox and most of water.Go up chromatogram purification at HP-20 resin column (2.5 centimetres of 18 cm x), use 100% water earlier, then use 1: 1 methyl alcohol: water elution, obtain title dilithium salt (0.180 gram, 79%), be white solid.
TLC(8: 1: 1 methylene dichloride: methyl alcohol: acetate).Rf＝0.16
(7: 2: 1 n-propyl alcohols: ammonia: R water) f=0.37
Embodiment 11
(R)-4-(((E)-2-(4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)-the 2-yl) vinyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
A.(E)-tributyl (2-(4 '-fluoro-3,3 ' 5-trimethylammonium (1,1 '-biphenyl)-the 2-yl) vinyl)-Xi
With reference to Miftakov, Synthesis(Comm such as M.A.) pp. 496-499(1985).
2-ethynyl-4 '-fluoro-3,3 ', 5-trimethylammonium (1,1 ' biphenyl) (1.7 gram, 7.13 mmoles) and tri-n-butyl stannane (2.9 milliliters, 10.7 mmoles, 1.5 the azobis isobutyronitrile (AIBN of mixture equivalent), 7.0 milligram, 0.426 mmole) to handle, solution quickly heats up to 120 ℃ (oil baths) under argon gas.At 120 ℃ after 15 minutes, add tri-n-butyl stannane (0.39 milliliter, 1.43 mmoles, 0.2 equivalent) again, continued to be heated to 3 hours altogether.The cooling yellow mixture obtains the vinyl stannane of 3.073 gram (81%) titles 0.1 mmhg, 240 ℃ with the Kugelrohr distillation purifying, is colourless liquid.
The TLC hexane, product R f=0.45, ultraviolet and phospho-molybdic acid.Product is unstable (colour band is dragged to baseline) on silica gel.
13C NMR（67.5MHz，CDCl 3）：9.5，13.6，14.5，20.9，21.1，27.2，27.6，114.0，114.3，123.6，123.9，128.8，130.4，133.0，135.6，136.1，138.1，140.0，144.4，160.3（J CF＝244H 2）ppm.
1H NMR：
δ0.8-1.5ppm（27H，m，Sn（Bu） 3）
2.27，2.31，2.36（9H，3 singlets，aromatic CH 3′s）
6.05（1H，d，J＝20Hz，PhCH＝CHSn）
6.68（1H，d，J＝20Hz，PhCH＝CHSn）
6.90-7.13（5H，m，aromatic protons）
B.(E)-4 '-fluoro-2-(2-iodoethylene base)-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)
Dry ether (20 milliliters) solution of the vinyl stannane of A part (1.537 grams, 2.89 mmoles) is handled with iodine (734 milligrams, 2.9 mmoles, 1 equivalent), this brown solution stirring at room 2 hours under argon gas.The mixture saturated sodium thiosulfate, anhydrous magnesium sulfate drying is used in 10% ammonium hydroxide and salt water washing, and evaporation obtains 1.639 gram yellow oil.Crude product is gone up purifying with the flash chromatography method at silica gel (160 gram), uses the hexane wash-out.Merge product and partly obtain the 832 milligrams of trans vinyl iodate of (65%) purified title things, be light yellow oil, leave standstill slowly crystallization, fusing point 53-55 ℃.
The TLC(hexane) trans alkene R f=0.31, (cis alkene R f=0.26), ultraviolet and phospho-molybdic acid
1H NMR（270MHz）：
δ2.30 & 2.32ppm（9H，2 singlets，aromatic methyls）
6.05（1H，d，J＝15Hz，-HC＝CHI）
6.92-7.10（5H，m，aromatic H′s）
7.24（1H，d，J＝15Hz，PhCH＝CHI）
13C NMR（67.5MHz）：14.6，21.0，21.1，81.0（＝CH-I），114.4，114.7，124.2，124.5，128.5，128.7，130.5，132.7，132.8，133.2，135.8，137.2，140.1，143.1（PhCH＝CHI），161.0（J CF＝244Hz）ppm.
Annotate: blending ingredients 1HNMR(CDCl 3, 270MH Z) show that close impurity is cis vinyl iodate thing, δ 6.54ppm(1H, d, JHaHb=7.9H Z(PhCHb=CHa-I)).
C.(R)-3-(((1, the 1-dimethyl ethyl) phenylbenzene-silyl) oxygen)-4-(((E)-2-(4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)-the 2-yl) vinyl)-the methoxyl group phosphinyl) butyric acid, methyl esters
(812 milligrams of the vinyl iodate things of the B part of past-78 ℃ (dry ice/acetone), 2.22 in dry tetrahydrofuran mmole) (6 milliliters) solution, drip (1.4 milliliters of the hexane solutions of 1.6M n-Butyl Lithium with syringe, 2.2 milligram, 1 equivalent) handles, this light yellow mixture is under argon gas, in-78 ℃ of stirrings 45 minutes, anion solutions is directly transferred in 10 minutes with dropper in-78 ℃ dry tetrahydrofuran (6 milliliters) solution of phosphonyl chloride (about 3.5 mmoles, 1.58 equivalents) of embodiment 1F part.The xanchromatic mixture stirred 30 minutes at-78 ℃, was warming to room temperature again.Add saturated ammonium chloride (5 milliliters) in the room temperature termination reaction.Mixture dilutes with ether, and the ether layer is used anhydrous magnesium sulfate drying with saturated ammonium chloride and salt water washing, and evaporation obtains 2.083 gram yellow oil.Crude product is with flash chromatography method purifying on silica gel, with (85: 15) hexane-acetone wash-out.Merge the product part, evaporation obtains 249 milligrams (17%) required trans alkene phosphinate, is light yellow oil.Nuclear magnetic resonance spectrum shows that product is the mixture of the diastereomer of about 1: 1 phosphate potential.TLC(7: 3) hexane-acetone, R f=0.35, ultraviolet and phospho-molybdic acid (PMA)
1H NMR：
δ3.27ppm（3H，d，J H-P＝11.6Hz， ）
3.57 ﹠amp; 3.60(3H, 2 singlets, diastereomer
-CO 2CH 3）
4.33 ﹠amp; 4.50(1H, 2 multiplets, diastereomer,
-CH 2CH（OSiR 3）CH 2-）
4.84 ﹠amp; 5.25(1H, 2 dd ' s, diastereomer
J HaHb＝17.9Hz，J Ha-P＝25.3Hz，
）
D.(R)-4-(((E)-2-(4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)-the 2-yl) vinyl)-the methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl esters
Tetrahydrofuran (THF) (5.0 milliliters) solution of the silicon ether (249 milligrams, 0.370 mmole) of C part is used Glacial acetic acid (85 microlitres successively, 1.48 mmole, 4.0 equivalent) and the 1.0M tetrahydrofuran solution (1.1 milliliters, 1.1 mmoles, 3 equivalents) of fluoridizing four positive fourth ammoniums handle.The yellow mixture that obtains is stirred overnight at room temperature under argon gas.Mixture is used ethyl acetate extraction with cold water (10 milliliters) dilution.Organic phase is used anhydrous sodium sulfate drying after washing with saturated brine, and evaporation obtains 243 milligrams of yellow oil.Crude product is with flash chromatography method purifying on silica gel, with (55: 45) hexane-acetone wash-out.Merge the product part, evaporation obtains 121 milligrams of (75%) title hydroxyl diester, is colourless thickness oily matter.
TLC(6: 4) acetone-hexane, R f=0.26, ultraviolet and phospho-molybdic acid (PMA)
1H NMR：
δ1.8-2.06ppm（2H，m，
Figure 881036994_IMG188
）
2.30，2.35，
2.40(9H, 3 singlets, aromatic hydrocarbons
CH 3′s）
2.40-2.60（2H，m，-CH（OH）CH 2CO 2CH 3）
3.50+3.55(3H, 2 doublets, diastereomer
Figure 881036994_IMG189
，J H-P＝12Hz）
3.64（3H，s，-CO 2CH 3）
3.77+3.84（1H，2 doublets，
Diastereomer-CH(OH)-)
4.28+4.38(1H, 2 wide multiplets,
-CH（OH）-）
5.52(1H, 2 dd ' s, diastereomer
J HHCoupling
﹠amp; J HPCoupling
Figure 881036994_IMG190
6.90-7.10(5H, the aromatic hydrocarbons proton)
7.50（1H，multiplet.
Diastereomer and
J HHCoupling
J HPCoupling
Figure 881036994_IMG191
E.(R)-4-(((E)-2-(4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)-the 2-yl) vinyl)-the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
The hydroxyl diester of D part (121 milligrams, 0.279 mmole) De diox (2 milliliters) solution is with (0.98 milligram of excessive 1.0N lithium hydroxide, 0.98 mmole, 3.5 equivalent) handle, limpid light yellow mixture stirred 1.5 hours 50 ℃ (oil bath) under argon gas.Cooling mixture, dilute with water filters vaporising under vacuum.Residuum is dissolved in the minimum water, separates in the enterprising circumstances in which people get things ready for a trip spectrum of HP-20 resin (thick 8 centimetres of bed, 25 millimeters of column diameters) post, and water (200 milliliters), (80: 20) water-methanol are used (60: 40) water-methanol wash-out at last successively.Product part vaporising under vacuum, in water-soluble (50 milliliters), lyophilize obtains 91 milligrams of pure title dilithium salts, is the white lyophilized products of moisture absorption.
TLC(8: 1: 1) methylene dichloride: methyl alcohol: acetate, Rf=0.19, ultraviolet and phospho-molybdic acid (PMA)
Embodiment 12-24
Summarize and the step described in the embodiment of front according to preceding, can prepare following these compounds.
Figure 881036994_IMG193
Figure 881036994_IMG194
Embodiment 25
(S)-4-(hydroxyl methoxyl group phosphinyl)-3-(((1, the 1-dimethyl ethyl) diphenylmethyl silylation) oxygen) butyric acid, methyl esters, dicyclohexylamine (1: 1) salt
A.(S)-4-diisopropoxy phosphinyl)-3-(((1, the 1-dimethyl ethyl) diphenylmethyl silylation) oxygen) butyric acid, methyl esters
Embodiment 1F(2) Bu Fen iodide (45.1 mmoles, 21.70 grams) stirred 30 minutes under high vacuum.Add new distillatory phosphorous acid tris(1-methylethyl) ester (0.451 mole, 93.92 grams, 113.37 milliliters) by the gross, reaction mixture is under argon gas, and heated and stirred is 16.5 hours in 155 ℃ of oil baths.Mixture is cooled to room temperature.Excessive phosphorous acid tris(1-methylethyl) ester and volatile reaction product with molecular distillation (10 mmhg), carry out Kugelrohr distillation (0.50 mmhg, 100 ℃, 8 hours) again and remove.Product is further purified (95 millimeters of column diameters, 6 inches/Merck silica gel, the hexane/acetone with 6/3/1/toluene wash-out with the flash chromatography method.Flow velocity 2 inch per minutes are got 50 milliliters of effluent liquid), obtain 17.68 gram (33.96 mmoles, productive rate 75%) title phosphonic acids isopropyl esters, be limpid thickness oily matter.
TLC: silica gel R f=0.32(6: 3: 1 hexane/acetone/toluene).
1HNMR：（270MH Z，CDCl 3）
δ 7.70-7.65（m，4H）
7.45-7.35（m，6H）
4.57-4.44（m，3H）
3.59（s，3H）
2.94 and 2.88（2xd，1H J＝3.7Hz）
2.65 and 2.60（2xd，1H J＝7.4Hz）
2.24-1.87（Series of m，2H）
1.19 and 1.12（2xd，12H J＝6.3Hz）
1.01（s，9H）
B.(S)-4-(hydroxyl methoxyl group phosphinyl)-3-(((1, the 1-dimethyl ethyl) diphenylmethyl silylation)-oxygen) butyric acid, methyl esters, dicyclohexylamine (1: 1) salt
The phosphonic acids isopropyl esters of A part (30.5 mmoles, 10.66 grams) in 80 milliliters of dry methylene chloride, under argon gas, stirring at room.In this solution, drip two trimethyl silyl trifluoroacetamides (BSTFA) (32.8 mmoles, 8.44 grams, 8.71 milliliters) earlier, drip (10 minutes) trimethyl silyl bromines (TMSBr) (51.3 mmoles, 7.84 grams, 6.75 milliliters) again.After 20 hours, add 200 milliliter of 5% aqueous potassium hydrogen sulfate termination reaction, vigorous stirring 15 minutes in stirring at room.Water layer ethyl acetate extraction three times.Merge organic extraction, with the salt washing once, use dried over sodium sulfate, under vacuum, concentrate.Residuum is with twice of 50 milliliters of methylbenzene azeotropic.The precipitation that generates is suspended in the toluene, and filtering and concentrating filtrate is repeated azeotropic/filtration procedure.The filtrate that obtains is evaporated in a vacuum, takes out under high vacuum 5 hours again.The limpid thickness oily matter that produces is dissolved in 50 milliliters of dry pyridines, stirring at room under argon gas.In this filtrate, add earlier dicyclohexyl carbodiimide (DCC) (22.6 mmoles, 4.65 grams) by the gross, add methyl alcohol (41.0 mmoles, 1.31 grams, 1.67 milliliters) again.After 20 hours, reaction mixture filters in sintered glass funnel with Celite pad in stirring at room.Wash Celite pad with ethyl acetate, merging filtrate, vaporising under vacuum.Residuum is dissolved in ethyl acetate again, with 5% aqueous potassium hydrogen sulfate washed twice, with the salt water washing once.The organic extraction dried over sodium sulfate is filtered, filtrate concentrate the back with twice of methylbenzene azeotropic, be suspended in the toluene filtration.The filtrate reconcentration that obtains, azeotropic filters, and the filtrate that obtains is carried out vacuum-evaporation, and places 6 hours under high vacuum, obtains phosphonate monoester, is limpid heavy-gravity oily matter (10.2 grams, productive rate＞100%).
TLC: silica gel, Rf=0.50(7: 2: 1 n-propyl alcohol/ammonium hydroxide/water.) phosphonate monoester (1.21 grams were taken out under high vacuum 4 hours, obtained 1.16 grams (2.57 mmole)) is dissolved in 10 milliliters of dry ethers, drips dicyclohexylamine (2.65 mmoles, 0.481 gram, 0.528 milliliter) and handle.The homogeneous solution that obtains was placed 7 hours in room temperature, had remarkable crystal to generate.Mixture was stored 16 hours at-20 ℃, was warmed to room temperature then, filtered.Crystallization was taken out 18 hours with Vanadium Pentoxide in FLAKES under high vacuum with the washing of exsiccant cold diethyl ether.Follow under high vacuum, took out 4 hours, obtain 1.25 gram (1.98 mmoles, productive rate 77%) title dicyclohexyl amine salts, be the white powder solid at 45 ℃.Fusing point 155-156 ℃.
TLC: silica gel Rf=0.57(20% ethanol/methylene) 1H NMR:(270MHz, CDCl 3)
δ 7.71-7.65（m，4H）
7.40-7.32（m，6H）
4.02（m，1H）
3.52（s，3H）
3.28 and 3.22（m，1H）
3.11（d，3H J＝11Hz）
2.77-2.64（m，2H）
2.62-2.56（m，1H）
1.92-1.08（Series of m，22H）
1.00（S，9H）
Mass Spec：（FAB）632（M&H） +
IR：（KBr） 3466-3457（broad）
3046，3016，2997，2937，2858，2836，2798，2721，2704，2633，2533，2447，1736，1449，1435，1426，1379，1243，1231，1191，1107，1074，1061，1051，820CM-1
Ultimate analysis C 22H 31O 6PSiC 12H 23N:
Calculated value: C, 64.63; H, 8.61; N, 2.22
Measured value: C, 64.51; H, 8.49; N, 2.18
Embodiment 26
(E)-4-((2-(4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl) the 2-yl) vinyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
A. (2-(4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)-the 2-yl)-the 2-hydroxyethyl)-phosphonic acids, dimethyl ester
(1.8 milliliters of the dimethyl methyl phosphonates of past-78 ℃ (dry ice/acetone), 16.5 mmole, 1.6 in dry tetrahydrofuran equivalent) (20 milliliters) solution, in 20 minutes, drip (9.7 milliliters of the hexane solutions of 1.6M n-Butyl Lithium, 15.5 mmole, 1.5 equivalent) handle, the white suspension of generation stirred 60 minutes at-78 ℃ under argon gas.Dry tetrahydrofuran (10 milliliters) solution of embodiment 1C xenyl aldehyde (2.5 grams, 10.3 mmoles, 1 equivalent) was partly splashed into wherein under-78 ℃ in 15 minutes, obtain light orange suspension.At-78 ℃ after 30 minutes, splash into saturated ammonium chloride (10 milliliters) in the mixture and termination reaction is warmed to room temperature.Mixture distributes between ethyl acetate and water, and anhydrous magnesium sulfate drying is used in organic phase salt water washing, and vacuum-evaporation obtains 4.127 gram yellow oil, leaves standstill slow crystallization.Crystallization is developed with hexane, obtains 3.38 gram (89.4%) pure title hydroxy phosphonates after filtration and the vacuum-drying, is the white needles thing, fusing point 98-100 ℃.From mother liquor (603 milligrams), use the flash chromatography method in addition, go up, use (7: 3) hexane-acetone wash-out at LPS-1 silica gel (40: 1), also recyclable 233 milligrams of pure title mixtures (3.613 restraining productive rate 95.6% altogether).TLC(1: 1) hexane-acetone, R f=0.33, ultraviolet+phospho-molybdic acid (PMA)
Ultimate analysis C 19H 24O 4PF:
Calculated value C, 62.29; H, 6.60; F, 5.19; P, 8.45
Measured value: C, 62.66; H, 6.56; F, 5.03; P, 8.68
B. (2-(4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)-the 2-yl) vinyl) phosphonic acids, dimethyl ester
The drying of the hydroxy phosphonate of A part (3.513 grams, 9.6 mmoles) is (with 4 Molecular sieve) toluene (15 milliliters) solution is with tosic acid-hydrate (pTSOHH 2O) (91 milligrams, 0.48 mmole, 0.05 equivalent) are handled, with being equipped with 4
Figure 881036994_IMG197
The Soxhlet device of molecular sieve refluxed 16 hours under argon gas.PTsOHH is appended at following interval in reaction process again 2O: 3.5 hours (91 milligrams), 5.0 hours (91 milligrams) and 6.5 hours (91 milligrams).Reaction mixture with the ethyl acetate dilution, with the saturated sodium bicarbonate washing, obtains the oil reservoir between water, organic phase and the two-phase.Collect water and oil reservoir, with the ethyl acetate washing, ethyl acetate layer washs with saturated sodium bicarbonate, puts earlier on one side.Ethyl acetate extraction is used in two batches of supercarbonate washings concentrated hydrochloric acid acidifyings, and anhydrous sodium sulfate drying is used in organic phase salt water washing, and evaporation obtains 520 milligrams of phosphonic acids that are recovered, mono-methyl.Oil reservoir is dissolved in trimethyl orthoformate (5 milliliters), and 4 hours renewable diester reflux under argon gas.Excessive manthanoate vacuumizes to be removed, and obtains yellow oil, it is dissolved in ethyl acetate and merges with former neutral organic phase.Anhydrous sodium sulfate drying is used in ethyl acetate layer salt water washing, and evaporation obtains 3.396 gram yellow oil, and thick oil is gone up purifying with the flash chromatography method at LPS-1 silica gel (40: 1), with (75: 25) hexane-acetone wash-out.The evaporate part obtains the trans vinyl phosphonic dimethyl phthalate of 2.987 gram (89.4%) titles, golden yellow oily matter.TLC(1: 1) hexane-acetone, R f=0.4, ultraviolet and phospho-molybdic acid.
1H NMR（CDCl 3）：
δ 2.27（3H，d，J H-F＝1.6Hz）
2.33（3H，s）
2.39（3H，s）
3.61（6H，d，J H-P＝11Hz）
5.51（1H，dd，J H-H＝18Hz，J H-P＝20.6Hz）
6.95-7.09（5H，m）
7.48（1H，dd，J H-H＝17.9Hz，J H-P＝23.7Hz）
ppm.
13C NMR（CDCl 3）：
δ 14.4，20.9，52.0（J C-P＝5.7Hz）
114.4，114.7，119.2（J C-P＝185.5Hz）
124.3，124.5，128.4，128.5，129.0 130.6
130.9 132.6，132.7，134.6，137.1，141.0，
148.2，148.2（J C-P＝5.7Hz）
160.5（J C-F＝244.1Hz）
C. (2-(4 '-fluoro-3,3 ', 5-trimethylammonium (1,1 '-biphenyl)-the 2-yl) vinyl) phosphonic acids, diox (20 milliliters) solution of the vinyl phosphonic dimethyl phthalate of mono-methyl B part (2.895 grams, 8.31 mmoles), with (12.5 milliliters of 1.0N lithium hydroxide solutions, 12.5 mmole, 1.5 equivalents) to handle, the mixture of generation stirred 70 minutes with 75 ℃ (oil bath) under argon gas.Heat after 15 minutes, mixture becomes evenly, mixture is cooled to room temperature, be acidified to pH=1 with 1.0N hydrochloric acid (about 15 milliliters), with ethyl acetate extraction twice, anhydrous sodium sulfate drying is used in organic phase salt water washing, vacuum-evaporation obtains 2.663 gram (95.8%) title mono-methyls, is limpid, colorless oil.TLC:(8: 1: 1) methylene chloride-methanol-acetate, R f=0.57, ultraviolet and phospho-molybdic acid.
Mass Spec(M+H +=335 +Observe).
1H NMR（CDCl 3）：
δ 2.25（3H，d，J H-F＝1.6Hz）
2.33（3H，s）
2.39（3H，s）
3.53（3H，d，J H-P＝11Hz）
5.61（1H，dd，J H-H＝18Hz，J H-P＝20.6Hz）
6.90-7.12（5H，m）
7.38（1H，dd，J H-H＝18Hz，J N-P＝24Hz）ppm.
D.4-((2-(4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)-the 2-yl) vinyl) the methoxyl group phosphinyl)-the 3-ketobutyric acid, methyl esters.
With etheric acid (420 microlitres that heavily evaporate, 3.9 mmole, 1.3 equivalent) in 15 minutes, be added drop-wise to (being scattered in the mineral oil of under argon gas, stirring by 60% sodium hydride, 168 milligrams, 4.2 mmole, 1.4 equivalents) in the suspension of 0 ℃ (ice bath) that forms with dry tetrahydrofuran (10 milliliters).Producing clear solution stirred 15 minutes at 0 ℃, (2.25 milliliters of n-Butyl Lithium hexane solutions that in 10 minutes, add 1.6M then, 3.6 mmole, 1.2 equivalent) handle, xanchromatic two anion solutions, stirred 15 minutes at 0 ℃, be cooled to-78 ℃ then with standby phosphonyl chloride processing.
As follows, prepare phosphonyl chloride from C division header mono-methyl.(960 milligrams of the phosphonic acids mono-methyls of C part, 287 mmoles) dry methylene chloride (8 milliliters) solution is with the trimethyl silyl diethylamine (750 microlitres, 5.98 mmoles that heavily steam, 2 equivalents) handle limpid mixture stirring at room 1 hour under argon gas.The mixture vaporising under vacuum is taken out 15 minutes remaining thickness oily matter with benzene azeotropic (2 * 15 milliliters), vacuum pump.Oily matter is dissolved in exsiccant methylene dichloride (8 milliliters) and the exsiccant dimethyl formamide (1), is cooled to 0 ℃ (ice bath).In 5 minutes, under argon gas, handle toward wherein splashing into the oxalyl chloride (290 microlitres, 3.3 mmoles, 1.1 equivalents) that heavily steams.At 0 ℃ after 15 minutes, mixture is at stirring at room 45 minutes, vaporising under vacuum.Thick oil and exsiccant benzene azeotropic (2 * 15 milliliters), vaporising under vacuum, drying obtained the phosphonyl chloride crude product after 15 minutes, were light yellow oil.
Dry tetrahydrofuran (8 milliliters) solution of-78 ℃ phosphonyl chloride (about 2.9 mmoles, 1 equivalent) was dropwise transferred in 30 minutes in-78 ℃ two anion solutions of methyl acetoacetate with conduit in 30 minutes., in tenne reaction mixture, drip saturated ammonium chloride (8 milliliters) and make reaction terminating after 30 minutes-78 ℃ of reactions.Be warmed to room temperature.With the ethyl acetate dilution, with saturated sodium bicarbonate and salt water washing, use anhydrous sodium sulfate drying, vacuum-evaporation obtains 1.481 gram orange.Thick oil is with flash chromatography method purifying on Merck silica gel, earlier with (9: 1) hexane-acetone, use (1: 1) hexane-acetone wash-out again.Merge the product part, evaporation obtains 813 milligrams of (62.9%) title vinyl phospho acid diester, is the heavy-gravity light yellow oil.TLC(1: 1) hexane-acetone, R f=0.42, ultraviolet and phospho-molybdic acid.
1H NMR（CDCl 3）：
δ 2.28（3H，s）
2.34（3H，s）
2.40（3H，s）
3.15（2H，dd，J H-H＝4.7Hz，J H-P＝18.2Hz）
3.54（3H，d，J H-P＝11.6Hz）
3.63（2H，s）
3.72（3H，s）
5.57（1H，dd，J H-H＝17.9Hz，J H-P25.3Hz）
6.95-7.09（5H，m）
7.52（1H，dd，J H-H＝17.9Hz，J H-P＝22.7Hz）
ppm.
13NMR（CDCl 3）：
δ 14.0（J C-F＝3.9Hz），
20.6，45.3（J C-P＝85.9Hz），
49.6，50.9（J C-P＝5.8Hz），
5.18，113.6，115.0 121.4（J C-P＝128.9Hz）
123.6，124.7，128，187.7，129.5，130.3，
130.8，132.1，132.4，136.4，136.8，
138.2，140.7，149.2（J C-P＝4.9Hz），
160.3（J C-F＝245.1Hz），
166.7，194.4（J C-P＝4.9Hz）ppm.
E.(E)-4-((2-(4 '-fluoro-3,3 ', the 5-trimethylammonium-(1,1 '-biphenyl)-the 2-yl) vinyl) the methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl esters
Use solid NaBH 4(51 milligrams, 1.35 mmoles, 1 molar equivalent) handle the solution of 0 ℃ (ice bath) of the D ketone that is dissolved in anhydrous tetrahydro furan (4 milliliters) (585 milligrams, 1.35 mmoles) partly, then drip anhydrous CH 3The OH(1 milliliter, 3
Figure 881036994_IMG198
Molecular sieve), and under argon shield this yellow mixture was stirred 30 minutes in 0 ℃.In 0 ℃ of interpolation acetone reagent (6.5 milliliters), then add CC-4 silica gel (500 milligrams) this mixture reaction is stopped then.This suspension heat to room temperature, is filtered through sintered glass, with the ethyl acetate rinsing and under vacuum inspissation, obtain 607 milligrams of yellow oil.This oily crude product (30: 1) on the Merck silicagel column is that leacheate is purified with the flash chromatography method with the pure ethyl acetate.The evaporate cut obtains 340 milligrams (productive rate 57.6%) required faint yellow title oily alcohol.
The TLC(pure ethyl acetate), R f=0.19, UV+PMA.
Mass spectrum (observes M+H +=435)
1H NMR（CDCl 3）：
δ 1.90（2H，m）
2.27+2.28（3H，2 singlets）
2.34（3H，s）
2.39+2.40（3H，singlets）
2.56（2H，d），
3.52（3H，d，J H-P＝11.1Hz）
3.69+3.70（3H，2 singlets）
3.79+3.90（1H，2 doublets）
5.52+5.54（1H，2dd，J H-H＝18Hz，J H-P＝2.48Hz）
6.95-7.02（5H，m）
7.52-7.54（1H，2dd，J H-H＝18Hz，J H-P＝21.6
Hz）ppm.
13C NMR（CDCl 3）（R，S mixture）：
δ 14.3（J C-F＝3.9Hz）
20.8，35.4+35.8（J C-P＝100.6Hz）
42.0（J C-P＝12.7Hz）
50.7（J C-P＝6.8Hz）
56.5，63.2（J C-P＝3.9Hz）
113.8，115.3，122.9+123.2（J C-P＝122.1Hz）
123.8，128.2，128.7，129.0，130.4，131.4，
132.3，132.7，136.6，137.0，138.2，140.8，
148.2+148.8（J C-P＝4.9Hz）
160.5（J C-F＝245.1Hz）
171.8ppm.
F.(E)-4-((2-(4 '-fluoro-3,3 ', the 5-trimethylammonium-(1,1 '-biphenyl)-the 2-yl) vinyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
With excessive 1.0N LioH(2.3 milliliter, 2.3 mmoles, 3 equivalents) handle the E part diester (339 milligrams, the solution in the 0.781 mmole) Zai diox (8 milliliters), and under argon shield with this mixture in 50 ℃ (oil bath) heating 1.5 hours.Reveal white precipitate after 15 minutes.One side insulation one side H 2O dilutes this mixture, all dissolves until all solids, filters then.With filtrate vacuum-evaporation, with the least possible H 2O dissolves it, and on HP-20 resin post with pure H 2O → pure CH 3The linear gradient leaching of OH carries out chromatographic separation.The evaporate cut is dissolved in white residuum (50 milliliters) filtration, freeze-drying in the water, obtains 270 milligrams of title dilithium salts that (productive rate 82.7%) is required, and it is a white freeze-drying body of inhaling temperature.
TLC（8∶1∶1）CH 2Cl 2-CH 3OH-HOAC，
Rf＝0.33，UV+PMA.
For C 21H 22O 5The ultimate analysis of FP2Li+0.63 mole of water
(MW 429.57): calculated value: C, 58.71; H, 5.46; F, 4.42; P, 7.21
Measured value: C, 58.71; H, 5.70; F, 4.18, P, 6.96
1H NMR（CDCl 3）
δ 1.59（2H，multiplet）
2.24-2.37（2H，3 multiplet，J H-H＝8.5Hz+4.4Hz）
2.28（3H，doublet，J H-F＝1.8Hz）
2.30+2.39（6H，2 singlets）
4.14（1H，multiplet）
5.78（1H，J H-H＝17.9Hz，J H-P＝20.5Hz）
6.88-7.21（6H，multiplet）
Embodiment 27
4-((2-(4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)-the 2-yl) ethyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
A.4-((2-(4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)-the 2-yl) ethyl) the methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl esters
Use the 10%Pd/C(74 milligram, 25%(weight)) handle the described trans ethene phosphinate of example 6E part (297 milligrams) crossed through argon purge at CH 3The OH(6 milliliter) solution in, and with this black suspension on Pa Er (Parr) device in the H of 40psi pressure 2Shake is 3 hours under the gas.With filling diatomite filtration catalizer, with filtrate vacuum-evaporation to oily.With this oily matter crystallization, after filtration and the vacuum-drying, obtain 267 milligrams of phosphinate white crystalline solid that (productive rate 89.5%) is saturated by hexane.The TLC(ethyl acetate), Rf=0.20, UV+PMA.
1H NMR(CDCl 3, 270MHz), IR(KBr sheet) and mass spectrum (observes M+H +=437 +)
1H NMR（CDCl 3）：
δ 1.55-1.87（4H，m）
2.29+2.30+2.31（6H，3 singlets）
2.35（3H，d，J H-F＝2.1Hz）
2.52（2H，m）
2.78（2H，m）
3.50+3.55（3H，2 doublets J H-P＝4.3Hz）
3.71（3H，s）
3.86+3.91（1H，2 singlets）
4.25+4.39（1H，2 broad multiplets）ppm.
B.4-((2-(4 '-fluoro-3,3,5 '-trimethylammonium (1,1 '-biphenyl)-the 2-yl) ethyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
With excessive 1.0N LiOH(1.72 milliliter, 3 equivalents) handle the A part diester (250 milligrams, the solution in the 0.573 mmole) Zai diox (6 milliliters), and with this mixture under argon shield in 50 ℃ (oil bath) heating 1.5 hours.Reveal white precipitate after 15 minutes.Use H 2O dilutes this mixture, continues insulation simultaneously and all dissolves until all solids, filters then.With filtrate vacuum-evaporation, with the least possible H 2O dissolves white residuum, and on HP-20 resin post with pure H 2Pure CH is then used in O drip washing (until neutrality) 3Chromatographic separation is carried out in OH drip washing.With the vacuum-evaporation of product cut to white solid, with CH 3CN azeotropic (2 *), vacuum-drying obtains the white solid of 131 milligrams of (55%) required title dilithium salts.
TLC(8: 1: 1) CH 2Cl 2-CH 3OH-acetate, Rf=0.34, UV+PMA.
Ultimate analysis calculated value: C 21H 24O 5FPLi 2+ 0.95 mole of H 2O(MW437.30): C, 57.67; H, 5.97; F, 4.34; P, 7.08
Measured value: C, 57.67; H, 5.90; F, 3.92; P.7.39
1H NMR（CD 3OD+D 2O）：
δ 1.39-1.57（4H，multiplet）ppm
2.22-2.37（2H，multiplet）
2.26+2.38（6H，2 singlets）
2.31（3H，doublet，J H-F＝1.8Hz）
2.71-2.77（2H，multiplet）
4.13-4.20（1H，multiplet）
6.73-7.11（5H，multiplet，aromatic H′s）
Embodiment 28
(E)-and 4-((2-(3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indoles-2-yl) vinyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
A. (2-(3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indoles-2-yl)-and the 2-hydroxyethyl) phosphonic acids, dimethyl ester
In 15 minutes, drip (7.3 milliliters of the solution of 1.6M n-Butyl Lithium in hexane, 11.6 mmole, 1.5 equivalent) handle-78 ℃ (acetone/COs of dimethyl methyl phosphonate (1.35 milliliters, 12.42 mmoles, 1.6 equivalents) in anhydrous tetrahydro furan (20 milliliters) 2) solution, under argon shield, the white suspension that obtains was stirred 1 hour in-78 ℃.In-78 ℃ with example 7(E) solution of part indolal (2.183 gram, 7.76 mmoles) in anhydrous tetrahydro furan (8 milliliters) was added drop-wise in 10 minutes in the above-mentioned negatively charged ion suspension, and the greenish orange look suspension that will obtain stirred 30 minutes at-78 ℃.Drip saturated NH 4The Cl(10 milliliter) makes this mixture termination reaction, rise to room temperature, at H 2Distribute between O and ethyl acetate,, use anhydrous Na with salt water washing organic phase 2So 4Drying is also evaporated, and obtains 3.19 gram white solids.This solid crude product is developed with hot hexane, obtained 2.967 gram (94.3%) pure title hydroxy phosphonate white solids, fusing point is 161-162 ℃.
TLC(1: 1) hexane-acetone, Rf=0.29, UV+PMA.
Ultimate analysis calculated value C 21H 25O 4NPF:C, 62.21; H, 6.22; N, 3.46; F, 4.69; P.7.64
Measured value C, 62.34; H, 6.32; N, 3.30; F, 4.61; P.7.32
1H NMR（CDCl 3）：
δ 1.69+1.74（6H，2 doublets）
2.18+2.56（2H，2 multiplets）
3.61（1H）
3.67+3.71（6H，2 doublets，J H-P＝11Hz）
5.32（1H，m）
5.50（1H，m）
7.04-7.25（4H，m）
7.33-7.39（2H quartet）
7.52（2H，AB quartet）ppm.
13C NMR（CDCl 3）：
δ 21.1，21.3，33.1（J C-P＝136.3Hz）
48.3，52.6+52.7（J C-P＝5.7Hz）
62.1（J C-P＝3.8Hz）
112.5，114.3，115.1，115.4，119.5，120，
122，128.1，130.6，131.9，132.0，134.8，
134.9，135.2，161.8（J C-F＝246.1Hz）ppm.
B.(is anti-)-(2-(3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indoles-2-yl) vinyl) phosphonic acids, dimethyl ester
Use PTs OHH 2O(122 milligram, 0.1 equivalent) handle the hydroxy phosphonate (2.60 grams, 6.43 mmoles) of the A part that is dissolved in hot benzene solvent (20 milliliters), with this mixture under argon shield by being equipped with 4 The Soxhlet device of molecular sieve refluxed 1 hour.With the yellow solution cooling that obtains,, use saturated NaHCO with the ethyl acetate dilution 3(2 *) and salt water washing organic phase are used anhydrous Na then 2SO 4Drying is also evaporated, and obtains 2.47 gram yellow solid alkene crude products.In ethyl acetate-hexane, carry out recrystallization one time, get 2.238 gram (89.9%) pure trans vinylphosphonate title compounds, be faint yellow chip solid, fusing point 153-155 ℃ TLC(1: 1) hexane-acetone, Rf=0.33, UV+PMA.
Mass spectrum (observes M+H +388 +)
Ultimate analysis calculated value C 21H 23O 3PNF:C, 65.11; H, 5.98; N, 3.62; F, 4.90; P.7.99
Measured value C, 65.27; H, 6.03; N, 3.48; F, 5.11; P.7.98
1H NMR（CDCl 3）：
δ 1.67（6H，doublet）
3.68（6H，d，J H-P＝11.6Hz）
4.90（1H，septet）
5.73（1H，dd，J H-H（trans）＝18Hz，J H-P＝18.2Hz）
7.05-7.56（8H，m）
7.64（1H，dd，J H-H＝17.9Hz，J H-P＝23.7Hz）ppm.
13C NMR（CDCl 3）：
δ 21.7，47.8，52.2（J C-P＝5.7Hz）
111.8，115.4，115.7，118.5（J C-P＝43.5H）
120.1，120.2，123.4，128.2，130.5，130.7，131.1，131.7，135.9，137.9（J C-P＝7.6Hz）161.9（J C-F＝246Hz）ppm.
C.(is anti-)-(2-(3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indoles-2-yl) vinyl) phosphonic acids, mono-methyl
Vinyl phosphonic dimethyl phthalate (1.787 grams with the B part; 4.61 mmole) be dissolved in the Re diox (12 milliliters), with 1.0N LiOH(6.9 milliliter, 6.9 mmoles; 1.5 equivalent) handle, and under argon shield, heated 30 minutes in 75 ℃ (oil bath).With this mixture cooling, use the 1.0NHCl(8 milliliter) acidifying, with ethyl acetate (2 *) extraction, use H 2O(2 *) and the salt water washing, through anhydrous Na 2SO 4Drying is also evaporated, and obtains 1.859 gram yellow oil.This oily matter is dissolved in hot hexane, cooling, crystallization obtains 1.657 gram (96.1%) monoprotic acid faint yellow solids, and fusing point is 181-183 ℃.
Ultimate analysis calculated value C 20H 21O 3PNF:C, 64.02; H, 5.70; N, 3.73; F, 5.06; P, 8.25
Measured value: C, 64.02; H, 5.87, N, 3.64, F, 5.26, P.7.90.
TLC(20: 1: 1) CH 2Cl 2-CH 3OH-acetate R f=0.26,
UV+PMA
1H NMR（CDCl 3）：
δ 1.66（6H，doublet）
3.64（3H，doublet，J H-P＝11.6Hz）
4.89（1H，septet）
5.81（1H，dd，J H-H＝17.9Hz，J H-P＝18.5Hz）
7.06-7.64（9H，multiplet）ppm.
13C NMR（CDCl 3）：
δ 21.8，47.9，52.1（J C-P＝5.7Hz）
112.0，115.5，115.8，116.1，119.0（J C-P＝9.5Hz）
120.2，120.4，123.5，128.3，130.4，130.8，131.2，131.8，131.9，136.2，136.8
（J C-P＝7.6Hz）
161.9（J C-F＝246Hz）ppm.
D.4-methoxyl group phosphinyl ((2-(3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indoles-2-yl) vinyl))-and the 3-ketobutyric acid, methyl esters
Prepare phosphonyl chloride as follows.Handle C part phosphonic acids mono-methyl (1.564 grams, 4.19 mmoles, 1 equivalent) at dry CH with distilled diethylin trimethyl silane (1.05 milliliters, 8.38 mmoles, 2 equivalents) 2Cl 2Solution in (10 milliliters),
With this mixture under argon shield in stirring at room 1 hour.This mixture of vacuum-evaporation is dissolved in the benzene (20 milliliters), carries out vacuum-evaporation again, after the thickness oily matter that stays is taken out 15 minutes with vacuum pump, with this silylated carboxylic acid crude product at dry CH 2Cl 2(10 milliliters) and dry DMF(1 drip) in solution be cooled to 0 ℃, drip distilled (COCl) 2(400 milliliters, 4.61 mmoles, 1,1 equivalent) are handled, and stir 15 minutes at 0 ℃ under argon shield, then in stirring at room 45 minutes.This yellow mixture of vacuum-evaporation is dissolved in benzene (20 milliliters), carries out vacuum-evaporation again, and takes out 15 minutes with vacuum pump, obtains thickness yellow oily phosphonyl chloride crude product.With the solution of above-mentioned phosphonyl chloride in dry tetrahydrofuran (8 milliliters) in-78 ℃, dropwise transfer in 20 minutes by sleeve pipe in-78 ℃ of solution of methyl acetoacetate dianion, this methyl acetoacetate dianion, as described in example 26, be by methyl acetoacetate (590 μ l, 5.45 mmole, 1.3 (235 milligrams of dispersion liquids in 60%NaH oil equivalent),, 5.87 mmole, 1.4 equivalent), the 1.6M n-Butyl Lithium is (3.1 milliliters, 5.03 mmole, 1.2 equivalents), tetrahydrofuran (THF) (10 milliliters) preparation.This orange reaction mixture stirred 30 minutes at-78 ℃, dripped saturated NH then 4Cl stops reaction, then rises to room temperature.With this mixture at ethyl acetate and H 2Distribute between the O, use saturated NaHCO 3With salt water washing organic phase, use anhydrous Na 2SO 4Carry out drying, obtain 2.080 gram yellow oil after the distillation.With flash chromatography on the Merck silicagel column with (7: 3) CH 2Cl 2-ethyl acetate is a leacheate, and above-mentioned oily crude product is purified.Merging product fraction is also evaporated, and gets 519 milligrams (26.3%) required faint yellow oily thing of the trans phosphinate of title.TLC(1: 1) hexane-acetone, Rf=0.48, UV+PMA.
Mass spectrum (observes M+H +=472 +)
1H NMR（CDCl 3）：
δ 1.66+1.71（6H，2 doublets）
1.68（2H，m）
3.23（2H doublet）
3.54（3H，d）
3.72（3H，s）
4.90（1H，septet）
5.76（1H，dd，J H-H＝18Hz）
7.10-7.58（8H，m）
7.66（1H，dd，J H-H＝18Hz）ppm.
13C NMR（CDCl 3）：
δ 21.8，45.7（J C-P＝87.1Hz）
47.9，50.0，51.5（J C-P＝5.7Hz）
52.3，111.9，115.5，118.8（J C-P＝104.1Hz）
119.8，120.2，120.3，123.6，128.2，130.4，130.8，131.8，131.9，136.1，139.2
（J C-P＝5.6Hz）
161.9（J C-F＝246Hz）
167.0，194.6（J C-P＝3.8Hz）ppm.
E.(E)-and 4-((2-(3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indoles-2-yl) vinyl) the methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl esters
Use solid NaBH 4(42 milligrams, 1.1 mmoles) handle ketone (519 milligrams, 1.1 mmoles)-15 ℃ of (salt/ice bath) solution in dehydrated alcohol (3A molecular sieve, 8 milliliters) of D part, in-15 ℃ this yellow mixture are stirred 20 minutes under argon shield.Add acetone (0.5 milliliter) successively and CC-4 silica gel (500 milligrams) stops this mixture reaction.Rise to room temperature, filter.Use the ethyl acetate rinsing, obtain 512 milligrams of yellow spumescence products after the vacuum-evaporation.On the Merck silicagel column, use (4: 1) ethyl acetate-acetone and pure acetone drip washing successively with flash chromatography, above-mentioned spumescence crude product is purified.The evaporate fraction gets 317 milligrams (60.9%) required title alcohol yellow oil.
TLC(4: 1) ethyl acetate-acetone, Rf=0.21, UV+PMA.
Mass spectrum (is observed M+H +=4.74 +)
1H NMR（CDCl 3）：
δ 1.68（6H，doublet）
1.97（2H，m）
2.58（2H，d）
3.61（3H，d，J H-P＝11Hz）
3.68（3H，s）
3.95+4.04（1H，2 doublets）
4.40（1H，bm）
4.95（1H，septet）
5.78（1H，dd，J H-H＝17.4Hz，J H-P＝23.2Hz）
7.05-7.77（9H，m）ppm.
13C NMR（CDCl 3）：
δ 21.7，34.9+36.3（J C-P＝20.8Hz）
42.0（J C-P＝13.2Hz）
47.8，50.8（J C-P＝5.6Hz）
51.6，63.1（J C-P＝15.1Hz）
111.8，115.4，115.7，118.6，119.9+121.8
（J C-P＝18.9Hz）120.1，123.4，128.2，
130.6，130.7，131.1，131.7，131.9，135.8，
138.0+138.5（J C-P＝5.7Hz）
161.8（J C-F＝246.1Hz）
171.7，171.8ppm.
F.(E)-and 4-((2-(3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indoles-2-yl) vinyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
Stir down with 1.0N LiOH(1.95 milliliter, 3.5 equivalents) processing E part of hydroxyl diester (264 milligrams, the solution in the 0.558 mmole) Zai diox (6 milliliters), and under argon shield, heated 20 minutes in 70 ℃.Cool off this mixture, dilute with water filters, and vacuum-evaporation is dissolved in the less water (1-2 milliliter), uses H on the HP-20 post successively 2O(is until neutrality, 3-4 times of column volume) and (75: 25) CH 3OH-H 2O drip washing is with the said mixture chromatographic separation.The evaporate fraction in water-soluble (50 milliliters), is filtered, and freeze-drying gets 217 milligrams (85.1%) required title dilithium salt white freeze-drying body.
TLC(8: 1: 1) CH 2Cl 2-CH 3OH-acetate Rf=0.08, UV+PMA
Ultimate analysis calculated value C 23H 23O 5NPF2Li+1.62 mole H 2O
（MW 486.46）：
C，56.78;H，5.44;N，2.88;F，3.91;P，6.37
Measured value: C, 56.76; H, 5.64; N, 2.58; F, 3.60; P, 6.77
1H NMR（400MHz，CDCl 3）：
δ 1.67（6H，doublet）
1.73（2H，multiplet）
2.38（2H，doublet of AB quartet，J AB＝15Hz，J AX＝8Hz，J BX＝4.8Hz）
4.24（1H，multiplet）
5.06（1H，septet）
6.09（1H，J HH＝17.6Hz，J HP＝19.4Hz）
7.02-7.61（9H，multiplet）
Embodiment 29
(S)-and 4-((2-(1-(4-fluorophenyl)-3-(1-methylethyl)-1H-indoles-2-yl) ethyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
A.4-methyl-2-oxopentanoic acid, ethyl ester
4-methyl-2-oxopentanoic acid sodium salt (25 gram) is dissolved in the least possible H 2Among the O, being acidified to PH with dense HCl is 1, uses CH then 2Cl 2Extraction several times.With the saturated water of NaCl and use CH 2Cl 2Strip (2 *).With the organic phase of salt water washing merging, through anhydrous Na 2SO 4After drying and the evaporation, obtain 17.7 gram free acid thickness oily matter.
Handle the mixture of above-mentioned acid product (17.7 grams, 136 mmoles) in dry benzene (200 milliliters) with diazabicyclo undecane (DBU) (20.4 milliliters, 136.2 mmoles, 1 equivalent), produce thermopositive reaction and form gluey crystal salt.Handle said mixture with iodoethane (10.9 milliliters, 1 equivalent), mechanical stirring is 3 hours under argon gas.The sedimentary salt of filtering washs filtrate once with less water (50 milliliters) and salt solution, uses anhydrous Na then 2SO 4Dry.Benzene is removed in air distillation, and the yellow liquid that vacuum distilling is remaining gets 6.46 gram (35.1%) required transparent weak yellow liquids of title ester, and boiling point is 65-66 ℃ (5mmHg).TLC(9: 1) hexane-acetone, Rf=0.55, PMA(is light blue), mass spectrum (observes M+H +=159 +).
B.4-Valeric acid ethylester methyl-2-(2-phenyl hydrazono-)
Drip (in 5 minutes) phenylhydrazine (3.3 milliliters, 33.2 mmoles, 1.05 equivalents) and handle A part ethyl ester (5 grams, 31.6 mmoles) at dry CH 2Cl 2Solution in (30 milliliters), the gained yellow mixture (adds 4 in stirring at room under argon gas Molecular sieve) 3 hour.Use anhydrous Na 2SO 4Dry this mixture filters, and vacuum-evaporation gets 8.105 gram orange.This oily matter is that leacheate purify with hexane-ethyl acetate with the flash chromatography method on the LPS-1 silicagel column.The evaporate fraction obtains the geometrical isomer of 6.8 gram (86.7%) pure title hydrazones and 848 milligrams of (10.8%) title hydrazones.
Overall yield=97.5%
TLC(9: 1) hexane-acetone, R fGeometrical isomer=0.42+0.64, UV+PMA
Mass spectrum (observes M+H +=249 +)
C.3-(1-methylethyl)-and the 1H-Indoline-2-carboxylic acid, ethyl ester
At room temperature gas Hcl is fed B part track (6.8 grams, 27.4 mmoles) dehydrated alcohol (50 milliliters, through 3 Molecular sieve drying) the solution bubbling is 30 minutes.The feature of this thermopositive reaction be color by the red deep green that changes to again of xanthochromia, then produce NH 4The Cl precipitating action.In the presence of drierite ze (Drierite), this suspension was further stirred 20 minutes, be poured into then in the frozen water (50 milliliters).Remove ethanol under the vacuum, residuum is at ethyl acetate and H 2Distribute between the O.With ethyl ester (2 *) aqueous layer extracted, use H 2The organic phase that O and salt water washing merge is used anhydrous MgSO then 4Drying obtains 4.969 gram green solid after the evaporation.Above-mentioned solid crude product is dissolved in hot hexane, handles,, be concentrated into the volume of 30-50 milliliter, this yellow solution crystallization through the diatomite filtration of filling with Darco.The sedimentary xln of filter collection, with cold hexane rinsing, after the drying 4.34 gram (68.5%) pure title indoles white needles things, fusing point is 80-81 ℃, and has unanimity 1H NMR(CDCl 3, 270MHZ)
TLC(9: 1) hexane-acetone, Rf=0.42, UV+PMA.
Annotate: with the Rf of indoles is identical, but indoles has bright purple fluorescence.(observe M+H +=232 +)
Ultimate analysis calculated value C 14H 17NO 2: C, 72.70; H, 7.41, N, 6.06
Measured value: C, 72.67; H, 7.57; N, 6.00
D.1-(4-fluorophenyl-3-(1-methylethyl)-and the 1H-Indoline-2-carboxylic acid, ethyl ester
Handle C part indoles (3.937 grams with Red copper oxide (245 milligrams, 1.7 mmoles, 0.1 equivalent), 17 mmoles) and (9.34 milliliters of 1-bromo-4-fluorobenzene, 85 mmoles, 5 equivalents) at dry DMF(15 milliliter) in solution, under argon gas, refluxed 17 hours.Add bromide (9.34 milliliters, 5 equivalents) and Cu 2The O(245 milligram, 0.1 equivalent), continue to reflux 6 hours, add Cu again one time 2The O(730 milligram, 5.1 mmoles) and continue to reflux 60 hours.Steam DMF and excessive bromide under the vacuum, remaining orange is dissolved in ethyl acetate,, use saturated NaHCO through filling diatomite filtration 3With the salt water washing, use anhydrous Na then 2SO 4Drying gets 5.385 gram (97.2%) required title indoles crude products (orange) after the evaporation.
TLC(9: 1) hexane-acetone, Rf=0.29, UV+PMA.
E.1-(4-fluorophenyl)-the 3-(1-methylethyl)-1H-indoles-2-methyl alcohol
Dry cold diethyl ether under argon shield (0 ℃, ice bath, 24 milliliters) adds solid LiAlH 4(907 milligrams, 23.9 mmoles, 1.5 molar equivalents) then dripped the D solution of K-281 (5.185 grams, 15.9 mmoles) in dry ether (10 milliliters) partly in 10 minutes.Stir this mixture 1 hour at 0 ℃, drip H successively at 0 ℃ then 215%NaOH(910 μ l) and H O(910 μ l), 2The O(2.73 milliliter) reaction is stopped.Through anhydrous MgSO 4Filling the above-mentioned suspension of filtration on the diatomite, filtrate is steamed into transparent, colorless oil.This oily matter is slowly crystallization in hexane, and (3.771 grams+0.333 gram) obtains 4.10 gram (90.9%) pure title indanol white particulate crystallizations in two batches,
Fusing point is 81-82 ℃.
Mass spectrum (observes M+H +=284 +)
Ultimate analysis calculated value C 18H 18NOF:C, 76.30; H, 6.40; N, 4.94; F, 6.71
Measured value: C, 76.59; H, 6.31; N, 4.93; F, 6.49
F.1-(4-fluorophenyl)-the 3-(1-methylethyl)-1H-indoles-2-formaldehyde
With the dry trimethyl carbinol (4 Molecular sieve, 1.44 milliliters, 15.24 mmoles, 1 equivalent) handle Dess-Martin periodo alkane (Periodinane) (6.46 grams, 15.24 mmoles) at dry CH 2Cl 2Solution in (30 milliliters) stirs this mixture 15 minutes in room temperature under argon gas.In 10 minutes, drip E part indanol (3.599 grams, 12.7 mmoles) at dry CH 2Cl 2Solution in (13 milliliters).Under argon gas, this pale yellow mixture was stirred 30 minutes in room temperature.This reaction mixture is added Sulfothiorine (14.06 grams, 89 mmoles, 7 equivalents) at freshly prepd 1N NaHCO 3In the solution in (40 milliliters), stirred 10 minutes.Remove water, use 1.0N NaHCO 3(2 *), H 2O and salt water washing organic phase are used anhydrous Na then 2SO 4Drying gets 3.877 gram yellow oil after the evaporation.This oily crude product is that leacheate purify with (40: 1) hexane-ether with the flash chromatography method on the LPS-1 silicagel column.The evaporate fraction gets 3.118 gram (87.3% crude product productive rate) crude products.Roll into a ball through a recrystallization at hot hexane, get the white fluffy spicule of 2.643 gram (74%) pure title aldehyde,
Fusing point is 114-116 ℃.
Mass spectrum (observes M+H +=282 +), TLC(7: 3) hexane-ether, Rf=0.51, UV+PMA
Ultimate analysis calculated value C 18N 16NOF:C, 76.85; H, 5.73; N, 4.98; F, 6.75
Measured value: C, 76.87; H, 5.63; N, 4.89; F, 6.88
G.2-(2,2-dibromo vinyl)-the 1-(4-fluorophenyl)-the 3-(1-methylethyl)-the 1H-indoles.
In 10 minutes, drip CBr at-15 ℃ (salt/ice baths) 4(2.86 grams, 8.61 mmoles, 1.5 equivalents) are at dry CH 2Cl 2Solution-treated F part aldehyde in (10 milliliters) (1.615 grams, 5.74 mmoles) and triphenyl phosphine (4.52 grams, 17.22 mmoles, 3 equivalents) are at dry CH 2Cl 2Solution in (25 milliliters), under argon gas in-15 ℃ with the dark orange red solution stirring of gained 15 minutes.Add saturated NaHCO at-15 ℃ 3This mixture reaction is stopped, using CH 2Cl 2Saturated NaHCO is used in dilution 3With salt water washing organic phase, use anhydrous Na then 2SO 4Drying gets 8.9 gram red solid after the evaporation.Is that leacheate purify above-mentioned solid crude product with (100: 1) hexane-ether with the flash chromatography method on the LPS-1 silicagel column.The evaporate fraction, the faint yellow crystallization that gets 2.017 gram (80.6%) pure title vinyl dibromo compounds, fusing point is 123-124 ℃.
TLC(9: 1) hexane-ether, Rf=0.67, UV and PMA.
Mass spectrum (observes M+H +=438 +)
Ultimate analysis calculated value C 19H 16NFBr 2: C, 52.20; H, 3.69; N, 3.20; F, 4.35; Br, 36.56
Observed value: C, 52.25; H, 3.69; N, 3.18; F, 4.24;
H.2-ethynyl-1-(4-fluorophenyl)-the 3-(1-methylethyl)-the 1H-indoles. handle-78 ℃ of (CO with the solution (5.5 milliliters, 8.8 mmoles, 2.2 equivalents) of 1.6M n-Butyl Lithium in hexane 2/ acetone) dry tetrahydrofuran (10 milliliters) solution, and under argon gas, in 15 minutes, drip the solution of G part vinyl dibromo compound (1.749 grams, 4 mmoles) in dry tetrahydrofuran (10 milliliters).At-78 ℃ this yellow mixture was stirred 20 minutes, add saturated NH then 4The Cl(10 milliliter) reaction is stopped.After rising to room temperature, dilute this mixture, use saturated NH with ethyl acetate 4Cl and salt water washing organic phase are used anhydrous Na 2SO 4Drying gets the dark green brown oil of 1.216 grams after the evaporation.Is that eluent purify above-mentioned oily crude product with (300: 1) hexane-ether with flash chromatography on Merck silica gel.With the evaporation of product fraction, get the green fluorescence oily matter of 1.084 gram (97.5%) title indoles acetylene. 1H NMR(CDCl 3, 270, MHZ) show it is (18: 1) mixture of required acetylide and unwanted alkene end group compound.
TLC(50: 1) hexane-ether, Rf=0.55, UV+PMA
J.(S)-and 4-((2-(1-(4-fluorophenyl)-1-(1-methylethyl)-1H-indoles-2 base) ethynyl) the methoxyl group phosphinyl)-3-(((1, the 1-dimethyl ethyl) diphenylmethyl silylation) oxygen) butyric acid, methyl esters
Prepare phosphonyl chloride with following method by phosphonic acids mono-methyl, the dicyclohexyl amine salt of example 25.By dicyclohexyl amine salt (4.32 grams, 6.83 mmoles, 1.75 equivalents) regeneration free acid, above-mentioned amine salt is distributed between 1.0N HCl and ethyl acetate, usefulness 1.0N HCl(2 *) and salt water washing organic phase, use anhydrous Na then 2SO 4Drying, vacuum-evaporation obtain transparent thickness oily free acid (6.8 mmole).Handle above-mentioned phosphonic acids mono-methyl (6.8 mmole) at dry CH with distillatory trimethyl silyl diethylamine (1.72 milliliters, 13.7 mmoles, 2 equivalents) 2Cl 2Solution in (10 milliliters), with this clear solution under argon gas in stirring at room 1 hour.The vacuum-evaporation said mixture is evicted it from dry benzene (2 * 20 milliliters), and was taken out 15 minutes with vacuum pump.This is mixed in dry CH 2Cl 2(10 milliliters) and dry DMF(1 drip) in the sour crude product of silylation be cooled to 0 ℃ (ice bath), and in 5 minutes, drip distillation (COCl) 2(655 μ l, 7.5 mmoles, 1.1 equivalents) are handled.Under argon gas, the gained yellow mixture was stirred 15 minutes at 0 ℃, stirring at room 45 minutes.The vacuum distilling said mixture is evicted from benzene (2 * 20 milliliters), takes out 15 minutes with vacuum pump, obtains yellow thickness oily phosphonyl chloride crude product.
In 10 minutes, drip 1.6M n-Butyl Lithium hexane solution (2.44 milliliters, 3.9 mmoles, 1 equivalent) and handle-78 ℃ (COs of the indoles acetylene of H part (1.084 grams, 3.90 mmoles, 1 equivalent) in dry tetrahydrofuran (10 milliliters) 2/ acetone) solution, this red suspension stirred 30 minutes in-78 ℃ under argon gas.This anion solutions mixture is added drop-wise in-78 ℃ of solution of phosphonyl chloride in dry tetrahydrofuran (10 milliliters) by sleeve pipe in 30 minutes in-78 ℃.The dun mixture that obtains was stirred 30 minutes in-78 ℃, drip saturated NH then 4The Cl(10 milliliter) reaction is stopped.Rise to room temperature, at ethyl acetate and NH 4Distribute between Cl, use the salt water washing, anhydrous Na SO 4Drying gets 1.968 gram (71.1%) title ethynyl phosphinate light yellow oil after the evaporation
TLC(7: 3) hexane-acetone, Rf=0.25UV+PMA.
Mass spectrum (observes M+H +=710 +)
K.(S)-and 3-(((1, the 1-dimethyl ethyl) diphenylmethyl silylation) oxygen)-4-((2-(1-(4-fluorophenyl)-3-(1-methylethyl)-1H-indoles-2-yl) ethyl) the methoxyl group phosphinyl) butyric acid, methyl esters
Use the 10%Pt/C(238 milligram, 25%(weight)) handle the acetylene compound (950 milligrams) of J part at CH 3The OH(10 milliliter) the solution in through the argon gas purge, with this black suspension at H 2(1atm) stirs and spends the night under the atmosphere.With micropore (Millipore) polycarbonate filter (0.4 μ m) with give the strainer filtration catalizer, vacuum-evaporation filtrate gets a yellow oil.Is that leacheate purify above-mentioned oily crude product with (8: 2) hexane-ethyl acetate with flash chromatography on the Merck silicagel column.The evaporate level is got the 915 milligrams of saturated phosphinate white foam of (86.7%) pure title bodies.
TLC(4: 1) ethyl acetate-hexane, Rf=0.39, UV+PMA
Mass spectrum (observes M+H +=714 +)
L.(S)-and 4-((2-(1-(4-fluorophenyl)-3-(1-methylethyl)-1H-indoles-2-yl) ethyl) the methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl esters
Use Glacial acetic acid (280 μ l, 4.88 mmoles, 4 equivalents) and 1.1Mn-C successively 4H 9NF is at the THF(3.3 milliliter, 3.66 mmoles, 3 equivalents) in the silyl ether (915 milligrams, 1.22 mmoles) of solution-treated K part at the THF(10 milliliter) in solution, with this mixture under argon gas in stirred overnight at room temperature.Add ice-cold H 2The O(8 milliliter), uses the ethyl acetate extraction said mixture, use 5% KHSO 4(2 *), saturated NaHCO 3With salt water washing organic phase, use anhydrous Na 2SO 4Drying gets 955 milligrams of yellow oil after the vacuum-evaporation.Is that leacheate purify above-mentioned oily crude product with (1: 1) hexane-acetone with flash chromatography on the Merck silicagel column.The evaporate fraction gets 521 milligrams (85.5%) required faint yellow oily thing of title alcohol.
TLC(3: 2) acetone-hexane, Rf=0.21, UV+PMA
Mass spectrum (observes M+H +=476 +)
M.(S)-and 4-((2-(1-(4-fluorophenyl)-3-(1-methylethyl)-1H-indoles-2-yl) ethyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
With excessive 1.0N LiOH(3.7 milliliter, 3.7 mmoles, 3.5 equivalents) handle the L part diester (505 milligrams, the solution in the 1.06 mmole) Zai dioxs (10 milliliters), under argon gas in 65 ℃ (oil baths) with this mixture heating up 1.5 hours.Use H 2O dilutes this mixture, filters, and vacuum is steamed to light yellow solid.This solid crude product is suspended in small amount of H 2Among the O, on Hp-20 resin (the thick 15cm of bed, column diameter 25mm) chromatographic column, use H 2O drip washing to neutrality is used CH again 3OH drip washing is with above-mentioned crude product chromatographic separation.Collect the product fraction,, be dissolved in H then its evaporation 2The O(50 milliliter), freeze-drying gets 484 milligrams (95.4%) required title dilithium salt white freeze-drying body.
TLC(8: 1: 1) CH 2Cl 2-CH 3OH-acetate, Rf=0.39, UV+PMA
Ultimate analysis calculated value C 23H 25NO 5FP2Li+1.03 mole H 2O
（MW＝477.91）：C，57.80;H.5.72;N，2.93;F，3.97;P，6.48
Measured value: C, 57.80; H, 6.01; N.3.01; F, 3.93, P, 6.41
Embodiment 30
(S)-and 4-((2-(1-(4-fluorophenyl)-3-(1-methylethyl)-1H-indoles-2-yl) ethynyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
A.(S)-and 4-((2-(1-(4-fluorophenyl)-3-(1-methylethyl)-1H-indoles-2-yl) ethynyl) the methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl esters
Use Glacial acetic acid (320 μ l, 5.6 mmole .4 equivalents) and n-C successively 4H 9The 1.1M solution (3.8 milliliter, 4.17 mmoles, 3 equivalents) of NF in THF is handled the solution of silyl ether (987 milligrams, 1.39 mmoles) in dry THF (12 milliliters) of example 30J part, in room temperature this mixture stirring is spent the night under argon gas.Use ice-cold H 2The O(10 milliliter) dilutes this mixture, use ethyl acetate extraction.Use 5%KHSO 4(3 *), saturated NaHCO 3With salt water washing organic phase, use anhydrous Na then 2SO 4Drying, evaporation gets 1.0 gram yellow oil.TLC shows and has formed certain monoprotic acid, uses CH 2N 2Ethereal solution handle and to be converted into methyl esters.Make excessive CH with Glacial acetic acid 2N 2Reaction stops, and this mixture of vacuum-evaporation gets 1.012 gram brown oil.On the Merck silicagel column, use (8: 2) hexane-acetone (600 milliliters) and (1: 1) hexane-acetone drip washing that above-mentioned oily crude product is purified successively with flash chromatography.After the evaporation of product fraction, obtain the light brown oily matter of 516 milligrams of (78.7%) free title alcohol.
TLC（9∶1）CH 2Cl 2-CH 3OH，Rf＝0.41，UV+PMA
Mass spectrum (observes M+H +=472 +)
B.(S)-and 4-((2-(1-(4-fluorophenyl)-3-(1-methylethyl)-1H-indoles-2-yl) ethynyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
With 1.0N LiOH solution (3.8 milliliters, 3.8 mmoles, 3.5 equivalents) handle A part diester (516 milligrams, the solution in the 1.09 mmole) Zai dioxs (10 milliliters), under argon gas with this transparent mixture in 60 ℃ of (oil bath) heated and stirred 1.5 hours.This mixture of dilute with water filters, and vacuum-evaporation is dissolved in the least possible H with residue oily matter 2Among the O, upward use pure H at HP-20 resin chromatography post (the 15cm bed is thick, the 25mm column diameter) 2O drip washing (until neutrality) is then with (1: 1) H 2O-CH 3OH drip washing is with above-mentioned product chromatographic separation.Vacuum-evaporation product fraction is dissolved in H 2The O(50 milliliter) in, filter, freeze-drying gets 447 milligrams (82.3%) required title dilithium salt white freeze-drying body.
TLC(8: 1: 1) CH 2Cl 2-CH 3OH-acetate, R f=0.39, UV+PMA
Ultimate analysis calculated value C 23H 21O 5PNF2Li+2.27 mole H 2O(MW496.19): C, 55.67; H, 5.19; N, 2.82; F, 3.83; P.6.24
Measured value: C, 55.69; H, 5.37; N, 2.82; F, 3.85; P, 6.19
Embodiment 31
(S)-and 4-(((2,4-diformazan-6-((4-fluorophenyl) methoxyl group) phenyl) ethynyl) hydroxyl oxygen phosphino-)-3-hydroxybutyric acid, dilithium salt
A.1-(methoxymethoxy)-3, the 5-dimethyl benzene
Under argon gas in 10 minutes with 3, the THF solution (12 milliliters) of 5-xylenol (10.42 gram, 85.3 mmoles) is added drop-wise to the NaH(85.3 mmole) (give earlier washed) through pentane at the THF(150 milliliter) in be cooled in 0 ℃ the suspension.After above-mentioned phenol dropwises, reactant was stirred 10 minutes at 0 ℃, rose to the room temperature restir 20 minutes.In this phenates solution, add 42 milliliters of dry DMF, then slowly add 10 milliliters of the THF solution of brooethyl methyl ether (11.19 restrain 89.6 mmoles).Form white precipitate., slowly add 25 milliliters of 1N NaOH reaction is stopped after 2.5 hours in stirring at room.Method with rotary evaporation is removed THF from reaction mixture, with the solution that saturated Nacl solution dilution obtains, use extracted with diethyl ether then three times.The ether phase extraction liquid that merges is through Na 2SO 4Dry also filtration.Removing desolvates obtains orange.With flash chromatography with 5% ether/hexane be eluent with purification of products, obtain the transparent oily matter of title methoxymethyl (MOM) ether (12.0 gram, productive rate 85%).TLC R f=0.45(15% ether/hexane, silica gel)
Mass spectrum m/e 166(M +), 165(M +-H) -
B.2-(methoxymethoxy)-4,6-dimethyl-phenyl aldehyde
Under argon gas, Tetramethyl Ethylene Diamine (7.70 grams, 79.45 mmoles) is slowly added in the solution of n-Butyl Lithium (26.5 milliliters 2.5M hexane solutions) in hexanaphthene (30 milliliters).This solution is cooled to 0 ℃, and drips the MOM ether (11.00 grams, 66.21 mmoles) of A part in 20 minutes.After dropwising, reaction solution was stirred 30 minutes at 0 ℃, rose to the room temperature restir 10 minutes.Under argon gas, by addition funnel this anionic reactive liquid is added DMF(5.81 gram, 79.45 mmoles in room temperature) 100 milliliters of dry cyclohexane solutions in.In room temperature this reaction solution was stirred 2 hours, use the methyl alcohol termination reaction then.On rotatory evaporator, remove the reaction solution solvent, the orange of gained is dissolved in 1: 1 ether/water mixture.MgSO is used in water layer extracted with diethyl ether three times 4The dry extraction liquid of collecting.Filter, remove solvent, obtain orange.Is that leacheate is purified above-mentioned oily matter with flash chromatography with 20% ether/hexane, obtains the transparent oily matter of required title aldehyde (7.7 grams, 60%).
TLC R f=0.14(15% ether/hexane, silica gel)
Mass spectrum m/e 195(M+H) +, 179(M-CH 3) +, 163(M-OCH 3) +, 149(M-OC 2H 5) +
C.2-hydroxyl-4, the 6-dimethylbenzaldehyde
(6.89 grams are in 35.5 mmole) De diox (130 milliliters) solution in room temperature 1M HCl solution (35.5 milliliters) to be added B MOM-ether partly.
This reaction solution is warming up to gentle reflux and stirred 30 minutes.Be cooled to room temperature, remove diox by rotary evaporation.Use H 2The aqueous solution of O dilution gained, and use extracted with diethyl ether.Use the saturated water of NaCl then, extract again three times with ether.Merge ether extraction liquid, use MgSO 4Dry.Filter, remove solvent after, obtain the light green solid, be purified (4.01 grams, 75%) by recrystallization in hexane.
TLC R f=0.48(25% ether/hexane, silica gel) fusing point is 46-48 ℃
Mass spectrum m/e 151(M+H) +, 135(M-CH 3) +
D.2-((4-fluorophenyl) methoxyl group)-4, the 6-dimethylbenzaldehyde
Stirring C phenol (4.0 grams, 26.7 mmoles) and dry DMF(30 milliliter partly under argon gas) solution.At room temperature with solid K 2CO 3(4.43 grams, 32 mmoles) add above-mentioned phenol solution, are warming up to 60 ℃ then and keep 35 minutes.The orange solution of gained is cooled to room temperature, adds a fluoro benzyl bromide (5.55 grams, 29.3 mmoles) is warming up to 60 ℃ of stirrings 2 hours with above-mentioned reaction solution.In 50 milliliters of frozen water of reaction mixture impouring, several times with extracted with diethyl ether.Use MgSO 4The dry ether extraction liquid that merges filters, except that getting a yellow solid after desolvating.After flash chromatography (is leacheate with 15% ether/hexane) purification, obtain title benzyl oxide (4.48 grams, 60%) white solid.
TLC R f=0.34(25% ether/hexane, silica gel)
Mass spectrum m/e 259(M+H) +, 231(M-CHO) +, 109(M-C 7H 6F) +
E.1-(2, the 2-dibromo vinyl)-2,4-dimethyl-6-(phenyl methoxyl group) benzene
Under argon gas, in ice-salt bath, cool off 170 milliliters of dry CH of D part aldehyde (4.42 grams, 17.13 mmoles) 2Cl 2Solution.Add triphenyl phosphine (14.4 grams, 55.0 mmoles) to this cooling solution, and be stirred to all solids and all dissolve.In 12 minutes, add CBr by addition funnel 450 milliliters of CH of (8.52 grams, 25.7 mmoles) 2Cl 2Solution.After interpolation finishes, this orange reaction solution was stirred 1 hour 15 minutes at 0 ℃.With 60 milliliters of saturated NaHCO 3The aqueous solution stops reaction, and violent stirring.Take out water layer CH 2Cl 2Extracting twice.Use saturated NaHCO 3The aqueous solution is with the CH that merges 2Cl 2Solution washing is once used MgSO 4Drying is filtered, and obtains the brown solid (13 gram) of title dibromo compound.With flash chromatography (is leacheate with 2% ether/hexane) above-mentioned title dibromo compound is purified, get 5.49 gram (productive rate 77%) title dibromo compounds.
TLC Rf=0.28(2% ether/hexane, silica gel)
Mass spectrum m/e 413(M+H) +, 333,335(M-Br) +, 317(M-C 6H 4F), 109(M-C 10H 9OBr 2) +
F.1-ethynyl-2-((4-fluorophenyl) methoxyl group)-4, the 6-dimethyl benzene
70 milliliters of THF solution with E part dibromo compound (5.48 grams, 13.3 mmoles) under argon gas are cooled to-78 ℃.In 10 minutes, n-Butyl Lithium (the 2.5M solution in hexane, 10.6 milliliters, 26.5 mmoles) is added in the above-mentioned dibromo compound solution.At-78 ℃ this reaction solution was stirred 1 hour, use saturated NH at-78 ℃ then 4The Cl aqueous solution stops reaction.After reaction solution rises to room temperature, with 60 milliliters of H 2O dilutes it, with ether with the water layer extracting twice.Merge all organic layers, and use MgSO 4Drying is filtered, and removes solvent, gets the yellow solid of 3.8 gram title benzyloxy acetylene.With flash chromatography (is leacheate with 3% ether/hexane) purification title benzyloxy acetylene, get title acetylide white solid 2.76 grams (productive rate 85%).TLC Rf=0.17(2% ether/hexane, silica gel)
Mass spectrum m/e 255(M+H) +, 159(M-C 6H 4F) +, 109(M-C 10H 9O) +
G.(S)-and 4-(((2,4-dimethyl-6-((4-fluorophenyl) methoxyl group) phenyl) ethynyl) hydroxyl oxygen phosphino-)-3-(tert-butyl diphenyl siloxy-) butyric acid, dilithium salt
40 milliliters of THF solution with part acetylide (2.76 grams, 11 mmoles) under argon gas are cooled to-78 ℃.In 8 minutes, add n-Butyl Lithium (4.4 milliliters of 2.5M solution in hexane) at-78 ℃.Reaction solution stirred 40 minutes at-78 ℃.
Phosphonyl chloride (17.4 mmole) with embodiment 25 under argon gas is cooled to-78 ℃ in 60 milliliters of THF.In 8 minutes, add the ethynyl anionic compound of above-mentioned generation then.After 1 hour, use saturated NH-78 ℃ of stirrings in-78 ℃ 4The Cl aqueous solution stops above-mentioned reaction, and rises to room temperature.Use H 2O dilutes water layer, uses twice of extracted with diethyl ether.THF is removed from THF reaction liquid layer, and the gained orange is dissolved in the ether.Merge all diethyl ether solutions, use saturated NaHCO 3Solution washing once, with saturated NaCl solution washing once.Use MgSO 4Dry organic layer filters, and gets 9.4 gram title ethynyl phospho acid, is orange jelly except that after desolvating.With the above-mentioned ethynyl phospho acid crude product of flash chromatography (is leacheate with 5/1/4 hexane/toluene/ethyl acetate mixture) purification, get the transparent jelly of 4.23 gram title ethynyl phospho acid, productive rate is 56%.
TLC R f=0.28(5/1/4 hexane/toluene/ethyl acetate, silica gel)
Mass spectrum m/e609(M+H-C 6H 5) +, 255(C 14H 19SiO) +
H.(S)-and 4-(((2,4-dimethyl-6-((4-fluorophenyl) methoxyl group) phenyl) ethynyl) methoxyl group phosphinyl)-3-hydroxybutyric acid, methyl esters
Ethynyl phosphinate (0.455 gram, 0.66 mmole) with the G part under argon gas stirs in 10 milliliters of THF.At room temperature add acetate (0.16 gram, 2.66 mmoles), then in 5 minutes, drip n-C 4H 9The THF solution of NF(1.8 milliliter 1.1M, 20 mmoles).Stir after 24 hours under the room temperature, add 30 milliliters of frozen water reaction solution is stopped.Take out water layer, use twice of ethyl acetate extraction.From the reaction solution organic layer, remove THF, the oily matter of gained is dissolved in the ethyl acetate, and merges with the water layer extraction liquid.Use saturated NaHCO 3The aqueous solution with saturated Nacl solution washing once, is used Na then with this ethyl acetate solution washed twice 2SO 4Dry.Filter, remove and desolvate, get 0.40 gram title hydroxylated tolan base phosphinate oily matter.With flash chromatography (is leacheate with 100% ethyl acetate) the above-mentioned title hydroxylated tolan base phosphinate of purifying, obtain productive rate and be 79% title hydroxylated tolan base phosphinate.
TLC R f=0.56(7: 3 acetone/hexane, silica gel)
Mass spectrum m/c 449(M+H) +, 431(M-OH) +, 417(M-OCH 3) +
J.(S)-and 4-(((2,4-dimethyl-6-((4-fluorophenyl) methoxyl group) phenyl) ethynyl) hydroxyl oxygen phosphino-)-3-hydroxybutyric acid, dilithium salt
Add 1.4 milliliters of 1N LiOH solution in room temperature to 6.0 milliliters of dioxane solutions of the ethynyl phosphinate (0.191 gram, 0.43 mmole) of H part.Reacting liquid temperature rises to 55 ℃ and stirred 2 hours.Then reaction solution is cooled to room temperature and evaporate to dryness, obtains title compound.This title compound is purified on the HP-20 chromatographic column of 130mm * 30mm diameter, earlier with 100 milliliters of H 2O drip washing uses 1: 1CH then 3OH/H 2The drip washing of O mixed solution.Obtain 0.170 gram title compound white freeze-drying body (productive rate 91%).
TLC R f=0.37(7: 2: 1 nproH/NH 4OH/H 2O, silica gel)
Mass spectrum (FAB) m/e 421(M+H) +, 427(M+Li) +, 433(M+2Li) +
Ultimate analysis calculated value C 21H 20O 6FPLi 21.4H 2O:C, 55.09; H, 4.98; F, 4.15; P, 6.78
Measured value: C, 55.13; H, 5.25; F, 4.08; P, 6.91
Embodiment 32
(S)-and 4-(((2,4-dimethyl-6-((4-fluorophenyl) methoxyl group) phenyl) ethyl) hydroxyl oxygen phosphino-)-3-hydroxybutyric acid, dilithium salt
A.(S)-and 3-(((1, the 1-dimethyl ethyl) diphenylmethyl silylation) oxygen)-4-((2-(2-((4-fluorophenyl) methoxyl group)-4,6-3,5-dimethylphenyl) ethyl) methoxyl group phosphinyl) butyric acid, methyl esters
The ethynyl phosphinate (1.34 grams, 1.95 mmoles) of embodiment 31G part is stirred in methyl alcohol (12 milliliters), add pto 2(0.040 gram) fed this methanol solution bubbling 10 minutes with hydrogen, kept H with balloon then 2(gas) atmosphere.5 hours 15 minutes afterreactions of room temperature finish, and the argon gas bubbling is passed through this reaction soln.The diatomite filter bed of reaction solution in thin sintered glass funnel filtered, use the methanol wash catalyzer.From filtrate, remove and desolvate, get the transparent jelly of the 1.4 gram saturated phosphinates of title.With flash chromatography (is leacheate with 60% ethyl acetate/hexane) above-mentioned crude product being purified, is that leacheate is with not too pure fraction chromatographic separation again with 6/2.5/1.5 hexane/acetone/toluene then.Get the 1.17 gram saturated phosphinates of title (productive rate 86%)
TLC Rf=0.045 (80% ethyl acetate/hexane, silica gel), mass spectrum m/e 691(M+H) +, 659(M-OCH 3) +, 635(M-C 9H 19Osi) +
B.(S)-and 4-(((2,4-dimethyl-6-((4-fluorophenyl) methoxyl group) phenyl) ethyl) methoxyl group phosphinyl)-3-hydroxybutyric acid, methyl esters
Under argon gas in room temperature with the phosphinate (1.16 grams, 1.68 mmoles) of A part at the THF(25 milliliter) in stir.In this phosphinate solution, drip Glacial acetic acid (0.40 milliliter), in 5 minutes, drip n-C then 4H 9NF(4.6 milliliter 1.1M THF solution).At room temperature this reaction solution is stirred and spend the night (18 hours), with 50 milliliters of ice-water reaction is stopped then.After stirring several minutes, add saturated Nacl solution, separate each layer.The rotary evaporation organic layer is removed THF, and residuum is dissolved in ethyl acetate.With ethyl acetate extraction water layer twice, merge all ethyl acetate solutions, use saturated NaHCO 3Solution washing twice with saturated Nacl solution washing once, is used Na then 2SO 4Dry.Filter, remove and desolvate, get the transparent oily matter of 1.13 gram title hydroxyl phosphinates.With flash chromatography (is leacheate with 100% ethyl acetate) the above-mentioned crude product of purifying, obtain the transparent oily matter of title hydroxyl phosphinate, productive rate 83%.
TLC Rf=0.27(6: 4 acetone/hexane, silica gel)
Mass spectrum m/e 453(M+H) +, 343(M-C 7H 6F) +
C.(S)-and 4-(((2,4-dimethyl-6-((4-fluorophenyl) methoxyl group) phenyl) ethyl) hydroxyl oxygen phosphino-)-3-hydroxybutyric acid, dilithium salt
At room temperature with B phosphinate (0.594 gram partly, 1.3 mmole) in 19 milliliters of dioxs, stir, and under agitation add 1N LioH(4.0 milliliter) in room temperature, reacting liquid temperature rises to 55 ℃, 55 ℃ keep after 20 minutes down, form white heavy-gravity precipitation, add 4.0 milliliters of dioxs again, and gained suspension is stirred at 55 ℃.55 ℃ keep down adding 3 milliliters of H after 2.5 hours 2O, the reaction mixture bleach.55 ℃ keep down after 3 hours reaction solution being cooled to room temperature, remove diox and water by rotary evaporation, and remaining title diprotic acid white solid was placed 15 minutes under high vacuum.By the HP-20 resin, earlier with 100 milliliters of H 2O drip washing is then with 1: 1CH 3OH/H 2The drip washing of O solution is with above-mentioned title diprotic acid chromatography purification.Obtain title diprotic acid white freeze-drying body, productive rate 67%.
TLC Rf=0.36(7: 2: 1 n-propyl alcohol/NH 4OH/H 2O, silica gel)
Mass spectrum .m/e(FAB), 425(M+H) +, 437(M+H+2 Li) +.
Ultimate analysis calculated value C 21H 24O 6FP1.15H 2O:C, 55.19; H, 5.80; F, 4.16; P, 6.78
Measured value: C, 55.19; H, 5.80; F, 4.29; P.6.83
Embodiment 33
(S)-4-((2-((1,1 '-biphenyl)-the 2-yl) ethynyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
A.(S)-4-((2-((1,1 '-biphenyl)-the 2-yl) ethynyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, methyl esters
Under argon gas, in 19.6 milliliters of dry THF, stir in the phosphinate (1.61 mmoles, 0.985 gram) of room temperature with example 9, D part.Drip Glacial acetic acid (6.44 mmoles, 0.386 gram, 0.368 milliliter) successively and in 8 minutes, drip n-C 4H 9NF(4.84 mmole, 4.40 milliliters 1.1MTHF solution) handle above-mentioned solution.After at room temperature stirring 18 hours, make above-mentioned reaction mixture termination reaction with 30 milliliters of frozen water.Use the ethyl acetate extraction water layer.Merge organic extract liquid, use saturated NaHCO 3Solution washing twice with the salt water washing once, is used MgSO 4Drying is filtered and evaporation.Separate above-mentioned product with flash chromatography (50mm post, 6 " Merck silica gel, 40% acetone/hexane leacheate, 2 "/minute flow velocity).The enriched product fraction is used methylbenzene azeotropic, and vacuum-evaporation, the yellow thickness oily matter of 0.369 gram (0.991 mmole) title alcohol, productive rate 62%, (also obtaining 0.098 gram, 0.263 mmole, 16% not too pure product).
TLC: silica gel R f=0.35(50% acetone/hexane)
Mass spectrum CI m/e 373(M+H) +
B.(S)-4-((2-((1,1 '-biphenyl)-the 2-yl) ethynyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
Diester (0.739 mmole, 0.275 gram) with A part under argon gas stirs in 7.57 milliliters of dioxs, and with 1M LioH(2.22 mmole, 2.22 milliliters) processing.The reaction mixture that this is muddy heated 45 minutes in 55 ℃ of oil baths.This mixture is cooled to room temperature.Remove by rotary evaporation and high vacuum (90 minutes) and to desolvate.Resulting yellow foam is dissolved in 4 milliliters of distillation H 2O, and by the HP-20 chromatographic column (2.5cm * 19cm) carries out drip washing, collects 10 milliliters of fractions in per 1.4 minutes.Use H 2This chromatographic column of O drip washing is used 45/55 methyl alcohol/H then until collecting 15 fractions (no longer being alkaline) 2O drip washing, (lyophilize twice, and use P 2O 5Under high vacuum, handle after 16 hours) must 0.231 gram (0.649 mmole, 88% productive rate) title diprotic acid white freeze-drying body.
TLC: silica gel R f=0.55(7: 2: 1 positive acetone/NH 4OH/H 2O)
Mass spectrum (FAB m/e 345(M+H) +, 351(M+Li) +, 357(M+2 Li) +
Ultimate analysis calculated value C 18H 15O 5PLi 2+ 1.42 moles of H 2O
MW＝381.75：C，56.63;H，4.71;P，8.07
Measured value: C, 56.62; H, 4.70; P, 8.07
Embodiment 34
(S)-4-((2-(3, the 5-dimethyl (1,1 '-biphenyl)-the 2-yl) ethyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
A.3,5-dimethyl (1,1 '-biphenyl)-2-formaldehyde
By Aldrich(Cat.No.17,156-5) obtain the 3M diethyl ether solution of phenyl-magnesium-bromide.
Under argon gas, two palladium complexes (4.48 mmoles, 3.35 grams) of example 1, B part and the mixture of triphenyl phosphine (35.85 mmoles, 9.40 grams) were stirred 30 minutes in 67.2 milliliters of dry toluenes in room temperature.This reaction mixture is cooled to 0 ℃, and past (promptly) wherein in batches adds phenyl-magnesium-bromide Grignard reagent (Aldrich) (35.84 mmoles, 11.95 milliliters 3M diethyl ether solution).Stirring at room 1.5 hours.Mixture is cooled to 0 ℃ then, and a collection of with 22.4 milliliters of 6.0N Hcl() handle, at room temperature stirred 1 hour.Isolate water layer, use extracted with diethyl ether.Merge organic extract liquid, filter (washing), use the salt solution wash filtrate,, obtain a kind of yellow solid with methylbenzene azeotropic, vacuum-evaporation with ether through the diatomite filter bed.Desired product flash chromatography (95mm diameter post, 6 " Merck silica gel, 100% hexane → 3% ether/hexane leacheate; 2 " / minute flow velocity) purifies twice, get 2.95 gram yellow solids (1.88 grams, 8.96 mmoles, the title aldehyde of 100% productive rate and 1.06 gram triphenyl phosphines).This mixture directly is used for preparing the compound of B part.
TLC: silica gel, Rf=0.30(5% ether/hexane)
Mass spectrum (CI) m/e 211(M 1+ H) +, 263(M 2+ H) +, 473(M 1+ M 2+ H) +
M 1The aldehyde of=A part, M 2=triphenyl phosphine.
B.2-(2, the 2-dibromo vinyl)-3, the 5-dimethyl-(1,1 '-biphenyl)
At-5 ℃ of aldehyde (8.96 mmoles, " 1.88 gram ") and triphenyl phosphine (26.4mmol, 6.90 restrain) with A part at 88 milliliters of dry CH 2Cl 2In mixture stirred 10 minutes.This reaction mixture is remained on-5 ℃, drip CBr simultaneously 4(13.2 mmoles, 4.38 grams) are at 32 milliliters of dry CH 2Cl 2In solution (20 minutes).The reaction mixture of gained stirred 1 hour at-5 ℃, became secretly orange gradually.Use 85 milliliters of saturated NaHCO then 3The aqueous solution makes this mixture stopped reaction.Use CH 2Cl 2Aqueous layer extracted merges organic extract liquid, uses saturated NaHCO 3Solution washing once with the salt water washing once, is used MgSO 4Drying is filtered vacuum-evaporation.With CH 2Cl 2In crude product give and absorbing on the 25 gram Merck silica gel, and be placed on flash chromatography post (50mm diameter, 6 " Merck silica gel, 4%CH 2Cl 2/ hexane leacheate, 2 " purify/minute flow velocity), 2.18 gram (5.96 mmoles, 68% productive rate) title vinyl dibromide thickness colorless oil.
TLC: silica gel, R f=0.37(4%CH 2Cl 2, hexane)
Mass spectrum (CI) m/e 365/367/369(M+H) +
C.3,5-dimethyl-2-(1-proyl) (1,1 '-biphenyl)
Under argon gas, stir the solution of vinyl dibromide (5.74 mmoles, 2.10 grams) in 29.11 milliliters of anhydrous THF of B part, and be cooled to-78 ℃.Drip (in 20 minutes) n-Butyl Lithium (11.47 mmoles, 4.59 milliliters of 2.5M hexane solutions) and handle this solution, generate a deep purple solution.-78 ℃ further stir 1 hour after, in-78 ℃ with 25 milliliters of saturated NH 4The cl aqueous solution makes the mixture stopped reaction, rises to room temperature, and dilute with water was with 1: 1 ether/hexane aqueous layer extracted.Merge organic extract liquid, use MgSO 4Drying is filtered vacuum-evaporation.With flash chromatography (50mm post, 6 " Merck silica gel, 1% ether/hexane leacheate) separated product, 1.08 gram (5.23 mmoles, 91% productive rate) title acetylide colorless oil, become blueness at-20 ℃ after storing 16 hours.
TLC: silica gel, Rf=0.32(100% hexane)
Mass spectrum (CI) m/e 207(M+H) +
D.(S)-3-(((1, the 1-dimethyl ethyl) diphenylmethyl silylation) oxygen)-4-((2-(3, the 5-dimethyl (1,1 '-biphenyl)-the 2-yl) ethyl methoxyl group phosphinyl) butyric acid, methyl esters
Under argon gas, stir the solution of acetylene compound (4.61 mmoles, 0.950 gram) in 27.3 milliliters of dry THF of C part, and be cooled to-78 ℃.Drip (in 20 minutes) n-Butyl Lithium (4.61 mmoles, the hexane solution of 1.84 milliliters 2.5M), produce dark violet/brown solution.At-78 ℃ this reaction mixture is stirred 1 hour (reaction mixture becomes pulpous state), rise to 0 ℃ of restir 15 minutes (reaction mixture becomes the mulberry homogeneous solution again), be cooled to-40 ℃ (it is uniform still keeping) at last again.Then this acetylide anion solutions of-40 ℃ is dripped (in 25 minutes) and arrive example 1F inferior phosphonyl chloride (8.12 mmole) partly in the solution of 27.3 milliliters of dry THE, this THF solution stirs under argon gas in advance and is cooled to-78 ℃.After above-mentioned dropping process was finished, this dark orange reaction mixture stirred 1 hour at-78 ℃, then at-78 ℃ with 50 milliliters of saturated NH 4The cl termination reaction rises to room temperature, uses H 2The O dilution.Use the extracted with diethyl ether water layer, merge organic extract liquid, use saturated NaHCO 3Solution washing once with the salt water washing once, is used MgSO 4Drying is filtered vacuum-evaporation.With flash chromatography (50mm column diameter, 6 " Merck silica gel, 50% ethyl acetate/hexane leacheate, 2 "/minute flow velocity) product is separated, get 0.609 gram (0.945 mmole, 21%) title phosphinate gold orange look oily matter.
TLC: silica gel, Rf=0.32(50% ethyl acetate/hexane) mass spectrum (CI) m/e 639(M+H) +
E.(S)-4-((2-(3, the 5-dimethyl (1,1 '-biphenyl)-the 2-yl) ethyl) the hydroxyl oxygen phosphino-)-3-(tert-butyl diphenyl siloxy-) butyric acid, dilithium salt
Argon gas is blasted methyl alcohol (13 milliliters) solution 10 minutes of the acetylene phosphinate (1.37 mmoles, 0.876 gram) of D part.Add the 10%pd/c(0.315 gram), this reaction mixture is carried out Pa Er (Parr) hydrogenation under 40psi pressure.Behind the shake 24 hours, the diatomite filter bed of this reaction mixture in sintered glass funnel filters.With methanol wash diatomite filter bed, vacuum-evaporation filtrate, get 0.896 gram yellow oil, it is used flash chromatography (50mm column diameter, 6 " Merck silica gel; 40%-50% ethyl acetate/hexane leacheate) purify, get 0.680 gram (1.06 mmoles, 77% productive rate) saturated phosphinate weak yellow foam of title shape thing.By the not too pure product of 0.087 gram of getting back with this flash chromatography post of methyl alcohol drip washing.
TLC:R f=0.27, silica gel (50% acetone/hexane)
Mass spectrum (CI) m/e 643(M+H) +
F.(S)-4-((2-(3, the 5-dimethyl (1,1 '-biphenyl)-the 2-yl) ethyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
Under argon gas, in 12.65 milliliters of dry THF, stir in the phosphinate (1.03 mmoles, 0.66 gram) of room temperature with the E part.Drip Glacial acetic acid (4.12 mmoles, 0.247 gram, 0.236 milliliter) and n-C successively 4H 9NF(3.09 mmole, the THF solution of 2.81 milliliters of 1.1M) handle above-mentioned solution.After at room temperature stirring 16 hours, make this reaction mixture stopped reaction with 25 milliliters of frozen water.Use the ethyl acetate extraction water layer.Merge organic extract liquid, use saturated NaHCO 3Solution washing twice with the salt water washing once, is used MgSO 4Drying is filtered vacuum-evaporation.With flash chromatography (40mm post, 6 " Merck silica gel, 50% acetone/hexane leacheate) the above-mentioned product of purifying, 0.363 gram (0.898 mmole, 87% productive rate) title alcohol white solid.
TLC: silica gel, R f=0.30(50% acetone/hexane).
Mass spectrum (FAB) m/e 405(M+H) +
G.(S)-4-((2-(3, the 5-dimethyl (1,1 '-biphenyl)-the 2-yl) ethyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
Diester (0.878 mmole, 0.355 gram) with F part under argon gas stirs in 9 milliliters of dioxs, and with 1M LioH(2.63 mmole, 2.63 milliliters) processing.This uniform reaction mixture of heating in 55 ℃ of oil baths.After 10 minutes, this reaction mixture becomes white suspension 55 ℃ of stirrings.Add 9 milliliters of dioxs and 2 milliliters of H 2O heats this suspension 45 minutes at 55 ℃, is cooled to room temperature then.Remove by rotary evaporation and high vacuum (1 hour) and to desolvate.(18cm * 2.5cm) carries out drip washing by the HP-20 chromatographic column with the white solid of gained.Collected 10 milliliters of fractions in per 1.4 minutes.Use H 2This chromatographic column of O drip washing is used 1: 1 methyl alcohol/H then until collecting fraction 15 times 2O drip washing is through freeze-drying (3 times) with use P 2O 5After handling (4 * 8 hours) under the high vacuum, get 0.289 gram (0.744 mmole, 85% productive rate) title diprotic acid white freeze-drying body.
TLC: silica gel, R f=0.56(7: 2: 1, positive acetone/NH 4OH/H 2O) press C 20H 23O 5PLi 2+ 0.34 mole of H 2O(M.W.=394.31) carry out ultimate analysis,
Calculated value: C, 60.92; H, 6.05
Measured value: C, 60.95; H, 6.18
Mass spectrum (FAB) m/e 389(M+H) +
Embodiment 35
(S)-4-((2-(4 '-fluoro-3, the 5-dimethyl (1.1 '-biphenyl)-the 2-yl) ethyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
The A.(4-fluorophenyl) magnesium bromide
Magnesium scrap metal (44.35 mmoles, 1.08 grams) is used the flame drying, under argon gas, place 40 milliliters of anhydrous diethyl ethers to stir then.Under vigorous stirring, drip 1-bromo-4-fluorobenzene (40.3 mmole) to above-mentioned magnesium compound.Initiation reaction in Vltrasonic device is being enough to drip halogenide under the speed that keeps refluxing then.After bromide dropwises, in room temperature reaction mixture was stirred 20 minutes, then reflux is cooled to room temperature at last.This method obtains a kind of transparent gold orange Se Geliya solution, and it is the 0.91M diethyl ether solution that contains 40.32 mmole title Grignard reagents.
B.4 '-fluoro-3, the 5-dimethyl (1,1 '-biphenyl)-2-formaldehyde
Reference: Stockker etc., Journal of Med.Chem, 29,170-181 page or leaf (1986).
Under argon gas, the palladium complex (4.35 mmoles, 3.20 grams) of example 26, B part and the mixture of triphenyl phosphine (40.32 mmoles, 10.58 grams) were stirred 30 minutes in 67.2 milliliters of dry toluenes in room temperature.This reaction mixture is cooled to 0 ℃ then, (promptly) adds Grignard reagent (40.32 mmoles of A part in batches, 44.43 milliliter), the mixture of gained at room temperature stirred 1.5 hours, be cooled to 0 ℃ then, and with 27.75 milliliters a collection of adding of 6.0N HCl() handle, at room temperature stirred 1 hour.Separate water layer, use extracted with diethyl ether, the organic extract liquid of merging filters through the diatomite filter bed.Wash filter bed with ether, the extraction liquid with the salt water washing merges with methylbenzene azeotropic twice, removes and desolvates, and gets an orange/yellow solid.By flash chromatography (95mm column diameter, 6 " Merck silica gel; hexane drip washing; then with 3% ether/hexane drip washing; 2 " / minute flow velocity) separates title aldehyde, finally obtain the mixture of reaction products faint yellow solid (3.70 grams are inferred the title aldehyde and the 1.70 gram triphenyl phosphines that wherein contain 8.7 mmoles (1.99 gram), 100% productive rate) of required title aldehyde and triphenyl phosphine.This mixture is directly used in the compound of preparation C part.
TLC: silica gel, Rf=0.25(5% ether/hexane)
1H NMR：（270MHZ，CDcl 3）
2-dibromo vinyl)-4 C.2-(2, '-fluoro-3.5-dimethyl (1,1 '-biphenyl)
In-5 ℃ of aldehyde (8.70 mmoles, " 1.99 gram ") and triphenyl phosphine (26.1 mmoles, 6.85 restrain) with B part at 87 milliliters of dry CH 2Cl 2The middle stirring 10 minutes.This reaction mixture remains on-5 ℃, drips CBr simultaneously in 25 minutes 4(13.05 mmoles, 4.33 grams) are at 43 milliliters of dry CH 2Cl 2In solution, the reaction mixture of gained stirred 1 hour at-5 ℃, generated dark orange solution, used 80 milliliters of saturated NaHCO then 3The aqueous solution stops reaction.Use CH 2Cl 2With water layer extraction 4 times.Use saturated NaHCO 3The aqueous solution and salt solution wash respectively merging organic extract liquid each once.Use MgSO 4Dry CH 2Cl 2Extraction liquid mixes filtrate mutually with 25 gram Merck silica gel.Evaporating solvent is with flash chromatography (post of 50mm diameter, 6 " Merck silica gel, 4%CH 2Cl 2/ hexane leacheate, 2 "/minute flow velocity) the above-mentioned product that gives absorption of purifying, get 2.32 gram (6.04 mmoles, 69% productive rate) title sym-dibromoethane based compound colorless oil.
TLC: silica gel, Rf=0.43(5%CH 2Cl 2/ hexane)
Mass spectrum (CI) m/e383/385/387(M+H) +.
D.4 '-fluoro-3.5-dimethyl-2-(1-proyl) (1,1 '-biphenyl)
Under argon gas, stir the solution of C part sym-dibromoethane based compound (5.99 mmoles, 2.30 grams) in 33 milliliters of anhydrous THF, and be cooled to-78 ℃.Drip (in 25 minutes) n-Butyl Lithium (11.97 mmoles, 4.79 milliliters 2.5M hexane solution) and handle above-mentioned solution, generate deep purple solution.In-78 ℃ further stir 1 hour after, in-78 ℃ with 25 milliliters of saturated NH 4The Cl aqueous solution makes the said mixture stopped reaction, rises to room temperature, with 25 milliliters of H 2The O dilution.With 1: 1 ether/hexane aqueous layer extracted 4 times.Merge organic extract liquid, use Mgso 4Drying is filtered, evaporation.With flash chromatography (50mm post, 6 " Merck silica gel, 0.50% ether/hexane leacheate, 2 "/minute flow velocity) separated product, get 1.25 gram (5.57 mmoles, 93% productive rate) title alkynyl compounds colorless oil, after 20 ℃ of seasonings, become blueness.
TLC: silica gel, Rf=0.25(100% hexane)
Mass spectrum (CL) m/e 225(M+H) +
E.(S)-4-((2-(4 '-fluoro-3.5-dimethyl)
(1.1 '-biphenyl)-the 2-yl) ethynyl) the hydroxyl oxygen phosphino-)-3-(tert-butyl diphenyl siloxy-) butyric acid, methyl esters
Stir the solution of D part alkynyl compounds (5.24 mmoles, 1.18 grams) in 28 milliliters of dry THF down in argon gas, and be cooled to-78 ℃.Drip (in 25 minutes) n-Butyl Lithium (5.24 mmoles, 2.10 milliliters 2.5M hexane solution).So dark violet/brown that reaction mixture becomes stirs reaction mixture 1 hour at-78 ℃ then, is warming up to 0 ℃, stirs 10 minutes, is cooled to-78 ℃ again.In-78 ℃ this alkynyl compounds anion solutions is dripped (in 20 minutes) in the solution of inferior phosphonyl chloride (8.32 mmole) in 28 milliliters of anhydrous THF of embodiment 1F part then, the latter has been cooled to-78 ℃, stirs under argon gas simultaneously.After dropwising, dark orange reaction mixture is used saturated NH in-78 ℃ then in-78 ℃ of stirrings 1 hour 4The cl aqueous solution stops reaction, rises to room temperature, uses H 2The O dilution extracts water layer 4 times with ether.Merge organic extract liquid, use saturated NaHCO 3Each washing of the aqueous solution and salt solution is once used MgSO 4Drying is filtered, evaporation.With flash chromatography (50mm column diameter, 6 " Merck silica gel, 40% ethyl acetate/hexane leacheate, 2 "/minute flow velocity) separated product, get the green thickness oily matter of 0.730 gram (1.11 mmoles, 21% productive rate) title alkynyl phosphinate.
TLC: silica gel, Rf=0.36(50% ethyl acetate/hexane)
Mass spectrum (CI) m/e 657(M+H) +
F.(S)-4-((2-(4 '-fluoro-3.5-dimethyl-(1.1 '-biphenyl)-the 2-yl) ethyl) the hydroxyl oxygen phosphino-)-3-(tert-butyl diphenyl siloxy-) butyric acid, methyl esters
Argon gas is fed methyl alcohol (9.9 milliliters) the solution bubbling 10 minutes of the alkynyl phosphinate (1.04 mmoles, 0.685 gram) of E part.Add 10%pd/C 0.239 gram, this reaction mixture carries out Pa Er (parr) hydrogenation under 40psl.Behind the shake 24 hours, the diatomite filter bed filter reaction mixture in sintered glass funnel is used the methanol wash filter bed, and evaporated filtrate gets the green oily matter of 0.638 gram.With flash chromatography (40mm column diameter, 6 " Merck silica gel, 45% ethyl acetate/hexane leacheate, 2 "/minute flow velocity) purified product, get 0.530 gram (0.802 mmole, 77% productive rate) saturated phosphinate weak yellow foam of title shape thing.Also obtain 0.09 gram (0.136 mmole, 13%) not too pure product.
TLC: silica gel, Rf=0.30(50% ethyl acetate/hexane)
Mass spectrum (CI) m/e 661(M+H) +
G.(S)-4-((2-(4 '-fluoro-3.5-dimethyl-(1,1 '-biphenyl)-the 2-yl) ethyl) the methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl esters
Under argon gas, in 9.74 milliliters of anhydrous THF, stir in the phosphinate (0.794 mmole, 0.525 gram) of room temperature with the F part.Drip Glacial acetic acid (3.18 mmoles, 0.191 gram, 0.182 milliliter) and n-C successively 4H 9NF(2.38 mmole, 2.17 milliliters 1.1M THF solution) handle above-mentioned solution.After 16 hours, make the reaction mixture stopped reaction in stirring at room with 15 milliliters of frozen water.With ethyl acetate water layer is extracted 3 times.Merge organic extract liquid, use saturated NaHCO 3Solution washing twice is used Mgso 4Drying is filtered, evaporation.With flash chromatography (40mm diameter, 6 " Merck silica gel, 50% acetone/hexane leacheate, 2 "/minute flow velocity) the above-mentioned product of purifying.The enriched product fraction with the methylbenzene azeotropic evaporate to dryness, gets 0.281 gram (0.665 mmole, 84% productive rate) title alcohol white solid.Wherein there is a kind of impurity can be by 270MHZ 1H NMR observes, but its separation can't not observed yet in various TLC system.
TLC: silica gel, Rf=0.31(50% acetone/hexane)
1H NMR：（270MHE，CDcl 3）
Mass spectrum (CI) m/e 423(M+H) +
H.(S)-4-((2-(4 '-fluoro-3, the 5-dimethyl-(1,1 '-biphenyl)-the 2-yl) ethyl) the hydroxyl oxygen phosphino-)-3-hydroxybutyric acid dilithium salt
Under argon gas, the diester of G part (0.473 mmole stirs in the 0.20 gram) Zai diox (4.84 milliliters), and with 1M LiOH(1.42 mmole, 1.42 milliliters) is handled, in 55 ℃ of oil baths, heated this homogeneous reaction mixture.After 10 minutes, reaction mixture becomes white suspension 55 ℃ of stirrings.This mixture further kept 45 minutes in 55 ℃, was cooled to room temperature then.Remove by rotary evaporation and vacuum (1 hour) and to desolvate.The white foam body that obtains is dissolved in 4 ml distilled waters, and (16cm * 2.5cm) carries out drip washing on the Hp-20 chromatographic column.Collected 10 milliliters of fraction H every 1.4 minutes 2This chromatographic column of O drip washing, until collecting fraction 15 times, and then with 1: 1 methyl alcohol/H 2O drip washing is through freeze-drying (2 times) with through P 2O 2High-vacuum pump was handled after 11 hours, got 0.158 gram (0.389 mmole, 82% productive rate) title diacid white freeze-drying body.
TLC: silica gel, Rf=0.59(1: 2: 1, n-propyl alcohol/NH 4OH/H 2O)
Mass spectrum (FAB) m/e 395(M+H) +
Ultimate analysis calculated value: C 20H 22FO 5PLi 2+ 0.39 mole of H 2O
MW＝413.25：C，58.12;H，5.56
Measured value: C, 58.14; H, 6.09
Embodiment 36
(S)-and 4-((2-(5-(4-fluorophenyl)-3-(1-methylethyl)-1-phenyl-1H-pyrazoles-4-yl) ethynyl) the methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl esters
A, 4-fluoro-beta-oxobenzenepropanoic acid ethyl ester
With 60% sodium hydride (17.4 grams, 0.43 mmole) of dry hexane wash in mineral oil, vacuum-drying is handled with pure carbon diethyl phthalate (44.3 milliliters, 0.36 mmole), drips right-fluoro-phenyl methyl ketone (22 milliliters, 0.18 mole) then and handles.After adding about 10% above-mentioned phenyl methyl ketone, add 4 ethanol and begin to reflux, remaining right-fluoro-phenyl methyl ketone added with the speed that can keep reflux conditions in 1 hour.The yellow solid that generates is made slurry in dry ether (250 milliliters), refluxed under argon gas 3.0 hours again.
The above-mentioned reaction mixture of cooling in ice bath, with ether (200 milliliters) dilution, water (1.3 liters) is handled lentamente, all dissolves until all solids.Water is separated with organic phase, with 12N Hcl(32 milliliter) to be acidified to pH be 1.0, with extracted with diethyl ether (2 * 500 milliliters).With the organic extract liquid that salt solution (200 milliliters) washing merges, use anhydrous MgSO 4Drying is filtered evaporate to dryness.The above-mentioned crude product of underpressure distillation (3.5 millimeters) (44.0 gram) obtains even buttery title compound (24.88 grams, 65.8%).
TLC:Rf=0.46(silica gel, 4: 1 CH 2Cl 2: hexane)
B, 4-fluoro-α-(2-methyl isophthalic acid-oxopropyl)-β-oxobenzenepropanoic acid ethyl ester
With dry hexane will be in mineral oil 60% sodium hydride (10.3 grams, 0.26 mmole) washed twice, vacuum-drying, then at the argon gas low suspension in dry tetrahydrofuran (245 milliliters), and be cooled to 0 ℃ (ice-water bath).The compound (24.5 grams, 0.12 mole) that dripped the A part in 20 minutes is handled above-mentioned suspension, rises to room temperature, restir 30 minutes.Reaction mixture is cooled to 0 ℃ (ice-water bath), drips isobutyryl chloride (18.62 grams, 0.17 mole) and handle, rise to room temperature, stirred 3.0 hours.This mixture is cooled to 0 ℃ (ice-water bath), and water (200 milliliters) stops reaction, obtains a homogeneous solution, on rotatory evaporator most of tetrahydrofuran (THF) is steamed.Use the 10%HCl(37 milliliter) with aqueous phase as acidified to pH1.0, with extracted with diethyl ether (3 * 100 milliliters).With the organic extract liquid that salt solution (50 milliliters) washing merges, use anhydrous MgSO 4Drying is filtered, and evaporate to dryness gets an oily matter (36.85 grams
It is raw material and two kinds of other mixture of products.
TLC:Rf=0.46,0.33,0.20(silica gel, 4: 1-CH 2Cl 2: hexane, UV)
C, 5-(4-fluorophenyl)-the 3-(1-methylethyl)-1-phenyl-1H-pyrazoles-4-carboxylic acid, ethyl ester
The crude product (36.85 grams, 0.12 mole of ≈) of B part is dissolved in the Glacial acetic acid (151 milliliters), under argon gas, adds 97% phenylhydrazine (18.1 milliliters, 0.18 mole) in batches and handle, and at room temperature stirred 19 hours.In reaction mixture impouring water (350 milliliters),, use saturated NaHCO with ether (3 * 100 milliliters) extraction 3The organic extract liquid that solution washing merges is alkalescence until water layer, uses salt solution (500 milliliters) washing then, anhydrous MgSO 4Drying is filtered evaporate to dryness.
This dark orange (300 milliliters) in sherwood oil is steamed once, obtain a yellow solid.Develop this crude product with sherwood oil (100 milliliters), get 15.3 gram crude products, then go up (with 2: 1CH at silicagel column (LPS-1) 2Cl 2: hexane drip washing) chromatographic separation gets 11.53 gram pure products.With mother liquor (26.4 gram) with silica gel chromatographic column (LPS-1) chromatography and develop the gained compound, obtain in addition the required product of 7.12g (overall yield: 18.65 restrain or 44.1%).With a small amount of title compound recrystallization in ether-hexane mixed solution, obtain homogeneous solid, fusing point 92-93 ℃.
TLC:Rf=0.35(silica gel, 4: 1-CH 2Cl 2: hexane)
Ultimate analysis
Calculated value: C, 71.57; H, 6.01; N, 7.95; F, 5.39
Measured value: C, 71.62; H, 5.99; N, 7.91; F, 5.54
D, 5-(4-fluorophenyl)-the 3-(1-methylethyl)-1-phenyl-1H-pyrazoles-4-methyl alcohol
(3.67 restrain to lithium aluminum hydride in 1.5 hours under argon gas, 96.7 mmole) cooling in anhydrous diethyl ether (70 milliliters) is (0 ℃, ice-salt bath) drips the C solution of compound (11.53 grams, 32.7 mmoles) in anhydrous diethyl ether (142 milliliters) partly in the suspension.In 1.5 hours, make this light green suspension heat to room temperature, be cooled to 0 ℃ (ice-salt bath) then again, drip water (20 milliliters), reaction is stopped until no longer emitting gas.Dilute this heavy-gravity slurries with ether (100 milliliters), filter, with ethyl acetate (3 * 150 milliliters) thorough washing throw out.(organic extract liquid that (50 milliliters) washing merges is used anhydrous MgSO with salt solution 4Drying is filtered, and evaporate to dryness obtains cream-colored solid (10.3 grams, 100% thick productive rate).With 100 milligrams of crude products recrystallization in ether-hexane mixed solution, get 58 milligrams of title compound white crystals, fusing point 138-140 ℃.
TLC:Rf=0.01(silica gel, CH 2Cl 2)
Ultimate analysis
Calculated value: C, 73.52; H, 6.17; F, 6.12; N, 9.03
Measured value: C, 73.16; H, 6.15; F, 6.12; N, 8.90
MS（M+H） +＝311
E, 5-(4-fluorophenyl)-the 3-(1-methylethyl)-1-phenyl-1H-pyrazoles-4-formaldehyde
Crude product (10.2 grams with the D part,～32.7 mmoles) solution in dry methylene chloride (85 milliliters) is added to pyridinium chloro-chromate (21.23 grams rapidly, 98.4 mmole) in the solution in dry methylene chloride (125 milliliters), under nitrogen, stirred 4.0 hours in the dark brown solution of room temperature with gained.With ether (750 milliliters) dilution said mixture, and stirred 10 minutes.Decant goes out supernatant liquid, stays the tarry residuum, develops this residuum with methylene dichloride (2 * 100 milliliters).With ether (750 milliliters) methylene chloride extraction liquid, the extraction liquid of collecting is filtered through silicagel pad.The transparent filtrate of evaporate to dryness gets 10.0 gram crude products.
With above-mentioned crude product on silicagel column (BaKer, 60-200 order, 400 milliliters) with 4: 1-CH 2Cl 2: chromatographic separation is carried out in hexane drip washing, obtains solid title compound (9.6 grams, 95.2%).100 milligrams of products recrystallization in hexane is obtained analytical sample (72 milligrams, fusing point 108-110 ℃).
TLC:Rf=0.58(silica gel, CH 2Cl 2, UV)
Ultimate analysis
Calculated value: C, 74.01; H, 5.56; N, 9.09; F, 6.16
Measured value: C, 74.10; H, 5.52; N, 9.12; F, 6.29
MS（M+H） +＝309
F, 4-(2, the 2-dibromo vinyl)-the 5-(4-fluorophenyl)-the 3-(1-methylethyl)-the 1-phenyl)-the 1-1H-pyrazoles
(2.0 restrain with E compound partly under argon gas, 6.48 mmole) and triphenyl phosphine (5.10 the gram, 19.2 mmole) mixture in dry methylene chloride (30 milliliters) is cooled to-5 ℃--10 ℃ (ice-salt bath), dripping the solution of carbon tetrabromide (3.22 grams, 9.61 mmoles) in dry methylene chloride (10 milliliters) in 5 minutes handles.Reaction mixture stirred 15 minutes at 15-20 ℃, then the saturated NaHCO of impouring 3In (10 milliliters), and extract with methylene dichloride (3 * 50 milliliters).Use saturated NaHCO 3The organic extract liquid that the washing of (10 milliliters), salt solution (25 milliliters) merges is used anhydrous MgSO 4Drying is filtered evaporate to dryness.
Crude product mixture (9.33 gram) (LPS-1) on silicagel column is used CH 2Cl 2/ hexanes mixtures (1: 9,1: 1,4: 1) drip washing, carry out chromatographic separation, obtain solid title compound (2.75 grams, 91.6%).With the crystallization of a small amount of title compound samples weighed, obtain white crystals, fusing point 88-90 ℃.
TLC:Rf=0.85(silica gel, 4: 1-CH 2Cl 2: hexane)
Ultimate analysis
Calculated value: C, 51.75; H, 3.69; N, 6.04; F, 4.09
Br，34.43
Measured value: C, 51.96; H, 3.51; N, 5.97; F, 4.22
Br，34.77
MS（M+H） +＝465
G, 4-ethynyl-5-(4-fluorophenyl)-the 3-(1-methylethyl)-1-phenyl-1H-pyrazoles
The solution of compound (2.64 grams, 5.67 mmoles) in dry tetrahydrofuran (10.5 milliliters) with the F part under argon gas is cooled to-78 ℃ (dry ice-propanone), drips 1.6M n-Butyl Lithium/hexane (7.16 milliliters, 11.37 mmoles) and handles.The suspension of gained stirred dropping 25%NH 1 hour 20 minutes in-78 ℃ 4The Cl(10 milliliter) reaction is stopped, rising to room temperature.With ether (3 * 50 milliliters) extractive reaction mixture,, use anhydrous MgSO with the organic extract liquid that salt solution (20 milliliters) washing merges 4Drying is filtered, and evaporate to dryness obtains light brown solid title compound (1.79 gram).
Use (5: 95) ether on silicagel column: hexane drip washing with above-mentioned crude product chromatographic separation, obtains light golden rod yellow solid title compound (1.08 grams, 97.4%).With small sample recrystallization in hexane, obtain white fluffy crystallization, fusing point 106-108 ℃.TLC:Rf=0.70(silica gel, 1: 9 ether: hexane, launch twice).
Ultimate analysis
Calculated value: C, 78.92; H, 5.63; N, 9.21; F, 6.24
Measured value: C, 79.22; H, 5.53; N, 9.28; F, 6.23
MS（M+H） +＝305
H.(S)-and 3-(((1, the 1-dimethyl ethyl) diphenylmethyl silylation) oxygen)-4-(((5-(4-fluorophenyl)-3-(1-methylethyl)-1-phenyl-1H-pyrazoles-4-yl) ethynyl) the methoxyl group phosphinyl) butyric acid, methyl esters
Under argon gas, stirred 1.0 hours in the crude product phosphonic acids mono-methyl (2.77 grams, 5.55 mmoles) and the mixture of trimethyl silyl diethylamine (2.1 milliliters, 11.05 mmoles) in dry methylene chloride (10 milliliters) of room temperature with example 1, F part.With this mixture evaporate to dryness, with dry benzene (20 milliliters) azeotropic, dry 15 minutes of vacuum (pump).This thickness oily matter is dissolved in the dry methylene chloride (10 milliliters) again, adds a DMF and handle, be cooled to-10 ℃ (ice-salt bath), drip oxalyl chloride (530 μ l, 6.08 mmoles) and handle.Observe violent phenomenon of deflation, this dark yellow solution was stirred 15 minutes in-10 ℃, then in stirring at room 1.0 hours.With the reaction mixture evaporate to dryness, with benzene (20 milliliters) azeotropic, vacuum-drying,
(1.12 restrain with G compound partly under argon gas, 3.67 mmole) solution in dry tetrahydrofuran (9.0 milliliters) is cooled to-78 ℃ (dry ice-propanone), handle with 1.6M n-Butyl Lithium/hexane (2.3 milliliters, 3.67 mmoles), and stirred 30 minutes at-78 ℃.Under argon gas, above-mentioned phospho chlorine (phosphochloridate) is dissolved in dry tetrahydrofuran (6.5 milliliters), be cooled to-78 ℃ (dry ice-propanone), drip the acetylene anion solutions by sleeve pipe and handle, two solution all remain on-78 ℃ in the whole dropping process.Reaction mixture was stirred 30 minutes at-78-78 ℃, drip 25%NH 4The Cl(6.0 milliliter) termination reaction rises to room temperature then.Extract this mixture with ether (3 * 100 milliliters), use 25%NH 4The Cl(10 milliliter), the organic extract liquid that merges of salt solution (25 milliliters) washing, use anhydrous MgSO 4Drying is filtered evaporate to dryness.
Use (9: 1)-hexane on silicagel column: acetone drip washing with this crude product mixture (～4.2 gram) chromatographic separation, obtains light brown oily title compound (1.54 grams, 57.0%)
TLC:Rf=0.33(silica gel, 7: 3-hexane: acetone)
I, (S)-4-((2-(5-(4-fluorophenyl)-3-(1-methylethyl)-1-phenyl-1H-pyrazoles-4-yl) ethynyl) methoxyl group phosphinyl)-and the 3-hydroxybutyric acid, methyl esters
Use Glacial acetic acid (190 μ l, 3.24 mmoles) and 1MBu successively 4NF(2.54 milliliter, 2.54 mmoles) handle the solution of compound (593.9 milligrams, 0.81 mmole) in dry tetrahydrofuran (8.0 milliliters) of H part, and under argon gas in stirred overnight at room temperature.Reaction mixture is cooled to 0 ℃ (ice-water bath), uses 5%KHSO 4(8.5 milliliters) are handled, and extract with ethyl acetate (3 * 75 milliliters).Use 5%KHSO 4The organic extract liquid that the washing of (10 milliliters), salt solution (20 milliliters) merges is used anhydrous MgSO 4Drying is spent the night, evaporate to dryness.
Above-mentioned crude product is dissolved in the mixture of ether (14 milliliters) and dry tetrahydrofuran (10 milliliters), is cooled to 0 ℃ (ice-salt bath), handle, and stirred 3.0 hours at 0 ℃ with the excessive diazomethane that places ether.Drip Glacial acetic acid and make reaction mixture stopped reaction, evaporate to dryness, vacuum-drying.Use (1: 2) acetone on silicagel column: hexane drip washing with above-mentioned crude product chromatographic separation, obtains semi-solid title compound (325.6 milliliters, 80.6% productive rate).
Embodiment 37
(s)-and 4-((2-(5-(4-fluorophenyl)-3-(1-methylethyl)-1-phenyl-1H-pyrazoles-4-yl) ethynyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
With 1N LiOH(2.25 milliliter, 2.25 mmoles) (325mg, the solution in the 0.65 mmole) Zai diox (7.7 milliliters) stirred 1.5 hours 55 ℃ (oil bath) under nitrogen, stirring at room 16 hours for the compound of Processing Example 36.With the reaction mixture evaporate to dryness, and vacuum-drying.On HP-20 chromatographic column (1 " * 5 "), with distilled water (400 milliliters) and 50%CH 3The OH aqueous solution (500 milliliters) drip washing is with above-mentioned crude product chromatographic separation.Merge required fraction, evaporate to dryness and vacuum-drying.Solid product is dissolved in distilled water, and freeze-drying obtains the fluffy solid-state freeze-drying body (317.1 milligrams, 96.4%) of title product.
TLC:Rf=0.33(silica gel, 8: 1: 1-i-PrOH: H 2O: NH 4OH)
C 24H 22FN 2O 5P2Li1.3H 2O(effective molecular weight=505.861)
Ultimate analysis calculated value: C, 56.99, H, 4.90; N, 5.54; F, 3.75; P, 6.12
Measured value: C, 56.98; H, 5.17; N, 5.46; F, 3.90; P, 6.26
H 1-NMR Spectrum（400MHz，CD 3OD）：
δ 1.40（d，6H，J＝7Hz）
1.81-1.98（m，2H）
2.35（dd，1H，J＝9，15Hz）
2.48（dd，1H，J＝4，15Hz）
3.35（septet，1H，J＝7Hz）
4.42（m，1H）
7.08-7.41（m，9H）.
IR（KBr）：2173cm -1（C≡C）.
Embodiment 38
(E)-and 4-((2-(5-(4-fluorophenyl)-3-(1-methylethyl)-1-phenyl-1H-pyrazoles-4-yl) vinyl) the methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl esters
A. (2-(5-(4-fluorophenyl)-3-(1-methylethyl)-1-phenyl-1H-pyrazoles-4-yl)-and the 2-hydroxyethyl) phosphonic acids, dimethyl ester
In 15 minutes, drip solution-treated dimethyl methyl phosphonate (2.81 milliliter, 25.9 mmoles)-78 ℃ (COs in dry THF (50 milliliter) of 1.6M n-Butyl Lithium in hexane (15.2 milliliters, 24.3 mmoles) 2/ acetone) solution after about 15 minutes, stirs above-mentioned white suspension 1 hour in-78 ℃ under argon gas.In 10 minutes, drip the solution of pyrazoles aldehyde (5.0 grams, 16.2 mmoles) in dry THF (15 milliliters) of example 36E part, this yellow mixture was stirred 30 minutes in-78 ℃.Use saturated NH 4The Cl(20 milliliter) the said mixture reaction is stopped, rising to room temperature.With this mixture at H 2Distribute between O and the ethyl acetate,, use anhydrous Na with salt water washing organic phase 2SO 4Drying, evaporation gets 7.158 gram title beta-hydroxy phosphonic acid ester crude products (yellow foams).In hexane,, obtain pure title compound white crystals, fusing point 126-128 ℃ with the small sample crystallization.TLC:(1: 1) hexane-acetone, R f=0.27
Mass spectrum (observes M+H +=433 +)
Ultimate analysis calculated value C 22H 26O 4N 2PF:C, 61.10; H, 6.06; N, 6.48; F, 4.39; P, 7.16
Measured value C, 60.95; H, 6.06; N, 6.41; F, 4.22; P, 7.27 1H NMR(CDCl 3):
δ 1.42（6H，d）
1.94-2.40（2H，m）
3.29(1H, septet)
3.62+3.63(2 doublet, J H-P=11.1Hz)
3.91（1H，s）
5.11（1H，bm）
6.90-7.30（9H，m）ppm.
13C NMR（CDCl 3）：δ22.6，26.5，32.8（J C-P＝136.3Hz），52.1（J C-P＝5.7Hz），60.8，115.0，115.4，119.3，119.5，124.7，126.3，126.6，128.5，132.2，132.3，139.4，139.5，156.7，164.5（J C-P＝265Hz）ppm.
B.(E)-and (2-(5-(4-fluorophenyl)-3-(1-methylethyl)-1-phenyl-1H-pyrazoles-4-yl) vinyl) phosphonic acids, dimethyl ester
Use pTsOHH 2The O(304 milligram, 1.6 mmoles) handle the solution of A part of hydroxyl phosphonic acid ester crude product (7.158 gram) in dry benzene (40 milliliters), this mixture refluxed 2 hours by the Dean-Stark trap that has the 4A molecular sieve under argon gas.With this mixture cooling,, use saturated NaHCO with the ethyl acetate dilution 3(2 *) and salt water washing organic phase are used anhydrous Na then 2SO 4Drying, vacuum-evaporation gets 6.893 gram yellow oil.Develop this oily crude product with hexane, get 5.692 grams and be close to pure vinylphosphonate canescence crystallization.Recrystallization once gets 5.655 gram (84.2%, with respect to the overall yield of aldehyde) the pure trans vinylphosphonate white needles of title bodies, fusing point 143-144 ℃ in two batches in ethyl acetate-hexane.TLC(1: 1) hexane-acetone, R f=0.40
Mass spectrum (observes M+H +=415 +)
Ultimate analysis calculated value C 22H 24O 3PN 2F:C, 63.76; H, 5.84; N, 6.76; F, 4.58, P, 7.47.
Measured value C, 63.99; H, 5.95; N, 6.76; F, 4.54; P, 7.31.
1H NMR（CDCl 3）：
δ 1.42（6H，d）
3.27(1H, septet)
3.70（6H，d，J H-P＝11.0Hz）
5.67（1H，dd，J HH＝18.4Hz，J HP＝18.5Hz）
7.02-7.30（9H，m）
7.34（1H，dd，J HH＝18Hz，J HP＝24.3Hz）ppm.
13C NMR（CDCl 3）：δ21.8，27.1，52.1（J C-P＝5.7Hz），110.4（J C-P＝193.1Hz），114.7（J C-P＝24.6Hz），115.9，116.2，122.2，124.9，125.5，127.3，128.8，132.0，139.2，140.2（J C-P＝7.6Hz），142.1，158.0，163.4（J C-F＝249.8Hz）ppm.
C.(E)-and (2-(5-(4-fluorophenyl)-3-(1-methylethyl)-1-phenyl-1H-pyrazoles-4-yl) vinyl) phosphonic acids, mono-methyl
With 1.0N LiOH(7.3 milliliter) dimethyl phosphonate of treatments B part (2.0 grams, the solution in the 4.83 mmole) Zai dioxs (15 milliliters), and under argon gas, this mixture was refluxed 1 hour.Be cooled to room temperature, being acidified to pH with 1.0N HCl is 1, with ethyl acetate (2 *) extraction, with 1.0N HCl and salt water washing organic phase, uses anhydrous Na then 2SO 4Drying, vacuum-evaporation gets the monoprotic acid crude product, slowly crystallization from hexane when this product leaves standstill.Filter collection crystal, vacuum-drying gets 1.918 gram (99%) title monoprotic acid white crystals bodies, fusing point 168-170 ℃.In second
Recrystallization prepares analytical sample in acetoacetic ester-hexane.
TLC(8: 1: 1) CH 2Cl 2: CH 3OH: acetate, R f=0.40
Mass spectrum (observes M+H +=401 +)
Ultimate analysis calculated value C 21H 22O 3N 2PF:C, 62.99; H, 5.54; N, 7.00; F, 4.75; P.7.74
Measured value C, 62.95; H, 5.57; N, 6.87; F, 4.58; P, 7.58
1H NMR（CDCl 3）：
δ 1.40（6H，d）
3.26(1H, septet)
3.65（3H，d，J H-P＝11.6Hz）
5.74（1H，dd，J H-H＝17.9Hz，J H-P＝19.5Hz）
7.00-7.36（10H，m）
8.65（1H，bs）ppm.
13C NMR（CDCl 3）：δ21.8，27.0，51.8（J C-P＝6.3Hz），111.7（J C-P＝198.7Hz），114.6（J C-P＝24.6Hz），115.8，116.2，124.9，125.4，127.3，128.7，131.9，132.1，138.8（J C-P＝7.6Hz），139.2，142.0，157.9，162.9（J C-F＝249.8Hz）ppm.
D.(E)-and 4-((2-(5-(4-fluorophenyl)-3-(1-methylethyl)-1-phenyl-1H-pyrazoles-4-yl) vinyl) the methoxyl group phosphinyl)-the 3-ketobutyric acid, methyl esters
Adopt following consumption to prepare the dianion of methyl acetoacetate according to example 26 described methods: methyl acetoacetate (815 μ l, 7.53 mmole), the dispersion liquid of 60%NaH in oil is (324 milligrams, 8.11 solution (4.3 milliliter, 6.95 mmoles), the THF(15 milliliter of 1.6M n-Butyl Lithium in hexane mmole)).
At room temperature with phosphonic acids mono-methyl (2.317 gram, 5.79 mmoles) and trimethyl silyl diethylamine (TMSDEA) (1.45 milliliters, 11.6 mmoles) at CH 2Cl 2Solution stirring in (15 milliliters) 1 hour.Mixture is evaporated to dried, it is evicted from vacuum-drying with benzene (20 milliliters).Residuum is dissolved in dry CH 2CH 2In (15 milliliters), with (COCl) 2(555 μ l, 6.37 mmoles) and DMF(1 drip) handle, and at room temperature stirred 1 hour.With this mixture evaporate to dryness, it is evicted from vacuum-drying with benzene (20 milliliters).
With-78 ℃ (COs of above-mentioned phosphonyl chloride in dry THF (10 milliliters) 2/ acetone) solution was dropwise transferred to the methyl acetoacetate dianion in-78 ℃ of solution of dry THF (15 milliliters) by sleeve pipe in 20 minutes.In-78 ℃ this brown mixture was stirred 30 minutes, drip saturated NH then 4The Cl(10 milliliter) termination reaction rises to room temperature.With this mixture at H 2Distribute between O and the ethyl acetate, use the ethyl acetate strip aqueous, use saturated NaHCO 3With the organic phase that the salt water washing merges, use anhydrous Na then 2SO 4Drying, vacuum-evaporation gets the orange foams of 3.080 grams.With flash chromatography on the Merck silicagel column with (5: 3: 2) hexane: acetone: toluene is leacheate, and crude product is purified.
Merge the product fraction, evaporation gets 1.247 gram (43.2%) required faint yellow oily things of title β-oxo phosphonic acid ester.
TLC(4: 4: 2) acetone: hexane: toluene, R f=0.29
Mass spectrum (observes M+H +=499 +)
1H NMR（CDCl 3）：
δ 1.42﹠amp; 1.43(6H, 2 doublets)
3.24（2H，m）
3.27(1H, septet)
3.63（2H，m）
3.66﹠amp; 3.67(3H, 2 doublets, J H-P=11.6Hz)
3.72（3H，s）
5.72（1H，dd，J HH＝18.7Hz，J HP＝24.3Hz）
7.08-7.30（9H，m）
7.37（1H，dd，J HH＝18.0Hz，J HP-22.7Hz）ppm.
13C NMR（CDCl 3）：δ21.8，27.1，46.1（J CP＝84.1Hz），50.0，51.2（J C-P＝5.9Hz），52.3，112.6（J CP＝135.0Hz），114.5（J CP＝23.5Hz），116.0，116.3，124.9，125.4，127.4，128.8，132.0，132.1，139.1，141.4（J CP＝5.9Hz），142.5，158.2，163.1（J CF＝250.4Hz），167.1，194.9，195.0ppm.
E.(E)-and 4-((2-(5-(4-fluorophenyl)-3-(1-methylethyl)-1-phenyl-1H-pyrazoles-4-yl) vinyl) the methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl esters
Use NaBH 4(100 milligrams, 2.62 mmoles) handle ketone (1.304 grams, 2.62 mmoles)-15 ℃ of (salt/ice bath) solution in dehydrated alcohol (15 milliliters) of D part, and in-15 ℃ this mixture are stirred 15 minutes under argon gas.Add acetone reagent (0.3 milliliter), then add CC-4 silica gel (600 milligrams), this reaction is stopped, rising to room temperature, with the ethyl acetate dilution, filter, vacuum-evaporation gets the yellow foams of 1.46 grams.With flash chromatography on the Merck silicagel column with (85: 15) ethyl acetate: acetone is leacheate, and crude product is purified.The evaporate fraction gets 388 milligrams of pure title alcohol white foam bodies and 228 milligrams of not too pure products.Ultimate production is 616 milligrams (47%).
TLC(7: 3) ethyl acetate-acetone, R f=0.31
Mass spectrum (observes M+H +=501 +)
1H NMR（CDCl 3）：
δ 1.42（6H，d）
2.00（2H，m）
2.60（2H，d）
3.27（1H，d）
3.64（3H，d，J HP＝11.1Hz）
3.69（3H，s）
3.93﹠amp; 4.02(1H, 2 doublets)
4.42（1H，2broad singlets）
5.72（1H，dd，J HH＝18.0Hz，J H-P23.2Hz）
7.04-7.47（10H，m）ppm.
13C NMR（CDCl 3）：δ21.8，27.1，35.7 & 36.5（J CP＝100.3Hz），42.0，42.2，50.8（J CP＝5.7Hz），51.6，63.4（J CP＝20.8Hz），114.2 & 114.4（J CP＝128.7Hz），114.6（J CP＝20.8Hz），115.9，116.3，124.9，125.4，127.3，128.8，131.9，132.1，139.1，140.1&140.6（J CP＝5.7Hz），142.1，158.0，163.0（J CF＝251.6Hz），171.2，171.9ppm.
Embodiment 39
(S)-and 4-((2-(5-(4-fluorophenyl)-3-(1-methylethyl)-1-phenyl-1H-pyrazoles-4-yl) vinyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
With 1.0N LiOH(3.4 milliliter, 3.4 mmoles) diester of Processing Example 38 (487 milligrams, the solution in the 0.973 mmole) Zai diox (10 milliliters), with this mixture in 70 ℃ of heated and stirred 30 minutes.H is used in cooling 2The O dilution is filtered, and vacuum-evaporation is to pale solid.Crude product is dissolved in the least possible H 2Among the O, and (15cm bed, 25mm column diameter) uses H successively on HP-20 resin chromatography post 2O and (1: 1) CH 3OH-H 2Chromatographic separation is carried out in O drip washing.Vacuum-evaporation product fraction is dissolved in 75 milliliters of H 2Among the O, filter, freeze-drying gets 429 milligrams (87.3%) pure fluffy freeze-drying body of title dilithium salt white.
TLC（8∶1∶1）CH 2Cl 2-CH 3OH-HOAc，R f＝0.14
Ultimate analysis calculated value C 24H 24O 5N 2PFLi 2+ 1.16 moles of H 2O
（MW 505.233）：C，57.05;H，5.25;N，5.55;F，3.76;P，6.13
Measured value C, 57.05; H 5.18; N, 5.75; F, 3.89; P, 6.47
1H NMR（400MHz，CD 3OD）：
δ 1.39(6H, doublet)
1.71（2H，m）
2.35（2H，m）
3.36(1H, septet)
4.24（1H，m）
6.00（1H，dd，J HH＝17.6Hz，J HP＝19.4Hz）
7.07-7.35（10H，m）
Embodiment 40
(E)-and 4-((2-(5-(4-fluorophenyl)-3-(1-methylethyl)-1-phenyl-1H-pyrazoles-4-yl) ethyl) the methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl esters
A.(S)-3 butyric acid methoxyl group phosphinyl (((1, the 1-dimethyl ethyl) diphenylmethyl silylation) oxygen)-4-((2-(5-(4-fluorophenyl)-3-(1-methylethyl)-1-phenyl-1H-pyrazoles-4-yl) ethyl)), methyl esters
With the solution of compound (912.0 milligrams, 1.24 mmoles) in dry methyl alcohol (50 milliliters) of 10%Pd/C Processing Example 36H part, hydrogenation is spent the night under 50psi pressure in Pa Er (Parr) hydrogenator.Filter above-mentioned suspension with the diatomite filter bed, with the filtrate evaporate to dryness, vacuum-drying obtains even oily title compound (908.3 milligrams, 99.1%).
TLC:Rf=0.23(silica gel; 7: 3-hexane: acetone).
B.(S)-and 4-((2-(5-(4-fluorophenyl)-3-(1-methylethyl)-1-phenyl-1H-pyrazoles-4-yl) ethyl) the methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl esters
Under argon gas,, use Glacial acetic acid (0.29 milliliter, 4.94 mmoles) and 1.0M Bu successively in the solution of compound (908.3 milligrams, 1.23 mmoles) in dry tetrahydrofuran (1.2 milliliters) of stirring at room A part 4NF/ hexane (3.89 milliliters, 3.89 mmoles) is handled.In room temperature reaction mixture was stirred 20 hours, with frozen water (25 milliliters) dilution, with ethyl acetate (3 * 100 milliliters) extraction.Use saturated NaHCO 3The organic extract liquid that the washing of (15 milliliters), salt solution (25 milliliters) merges, drying (is used anhydrous MgSO 4), filter evaporate to dryness.
(LPS-1 on silicagel column; 1 " * 9.5 ") use ethyl acetate: hexanes mixtures (4: 1; 9: 1), ethyl acetate and acetone carries out drip washing, with above-mentioned crude mixture (1.0 gram) chromatographic separation, obtains oily title product (529.1 milligrams, 85.6% productive rate).
TLC:Rf=0.17(silica gel; 4: 1-ethyl acetate: hexane)
Embodiment 41
(S)-and 4-((2-(5-(4-fluorophenyl)-3-(1-methylethyl)-1-phenyl-1H-pyrazoles-4-yl) ethyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
With 1.0N LiOH(3.7 milliliter, 3.7 mmole) compound of Processing Example 40 is (529.0 milligrams, 1.05 the solution in the mmole) Zai diox (12.5 milliliters), and stirring 3.0 hours in 55 ℃ (oil bath) in nitrogen is then in stirring at room 20 hours.With the reaction mixture evaporate to dryness, and carry out vacuum-drying.On the Hp-20 chromatographic column (1 " * 6 "), with distilled water (750 milliliters), 10%CH 3The OH aqueous solution (500 milliliters), 20%CH 3The OH aqueous solution (500 milliliters) and 50%CH 3The OH aqueous solution (500 milliliters) drip washing is with above-mentioned thick product wealth chromatographic separation.Merge required fraction, evaporate to dryness, vacuum-drying.The solid of gained is dissolved in distilled water (35 milliliters), and freeze-drying obtains white fluffy solid title compound (510.0 milligrams, 92.4%).
TLC:Rf=0.38(silica gel, 8: 1: 1-i-prOH: NH 4OH: H 2O)
Ultimate analysis calculated value C 24H 26FLi 2N 2O 5P2.2H 2O(effective molecular weight .=525.899): C, 54.81; H, 5.83; N, 5.33; F, 3.61; P, 5.88
Measured value: C, 54.81; H, 5.61; N, 5.53; F, 4.06; P, 5.80
IR（KBr）（1596cm -1，C＝O of COO -）.
H 1-NMR composes (400MHz, CD 3OD):
δ 1.36（d，6H，J＝7）
1.60-1.72（m，4H）
2.32（m，2H）
2.74（m，2H）
3.21（septet，1H，J＝7）
4.23（m，1H）
7.06-7.32（m，9H）.
Embodiment 42
(S)-and 4-((2-(3-(4-fluorophenyl)-5-(1-methylethyl)-1-phenyl-1H-pyrazoles-4-yl) ethynyl) the methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl esters
A.4-fluorobenzoic acid, 2-phenyl hydrazides
Under nitrogen with (25 milliliters of phenylhydrazines, 0.25 mmole) and (35 milliliters of triethylamines, 0.25 mmole) mixture in anhydrous diethyl ether (500 milliliters) is cooled to-5--10 ℃ (cryosel bath), and dropping 4-fluorobenzene carbonyl chloride (30 milliliters, 0.25 mole) is handled said mixture in 30 minutes.This reaction mixture is risen to room temperature, stirred 3.0 hours, filter then, with the solid of ether (200 milliliters) thorough washing generation.This solid is dissolved in methylene dichloride (600 milliliters), is evaporated to, be suspended in the hexane (600 milliliters), filter near drying regime.With transparent filtrate evaporate to dryness,, filter the solid that obtains with tetrahydrofuran (THF) (100 milliliters) thorough washing with tetrahydrofuran (THF) (700 milliliters) development.With the filtrate evaporate to dryness, vacuum-drying obtains being mixed with the crude product (34.6 gram) of two kinds of other components.
This crude product recrystallization in acetone obtains title compound white crystals (22.36 grams, 38.8%), fusing point 182-184 ℃
Merging filtrate and mother liquor, (Baker, 60-200 order, 400 milliliters) are with (1: 9) ethyl acetate: CH on silicagel column 2Cl 2Mixture is a leacheate, with its chromatographic separation, obtains other 9.78 gram title compounds (55.8%)
TLC:Rf=0.63(silica gel, 1: 4-ethyl acetate: CH 2Cl 2)
Ultimate analysis calculated value: C 13H 11FN 2O:C, 67.81; H, 4.82; N, 12.17, F, 8.25.
Measured value: C, 67.86; H, 4.88; N, 12.14; F, 8.10
MS（M+H） +＝231.
B.4-fluoro-N-phenyl hydrazono-is for Benzoyl chloride
Handle the solution of compound (6.16 grams, 26.8 mmoles) in anhydrous diethyl ether (46 milliliters) of A part with phosphorus pentachloride (6.6 gram, 31.7 mmoles), with this reaction mixture refluxed under nitrogen 16.0 hours.Reaction mixture is cooled to room temperature, handles, stirred 5 minutes, drip methyl alcohol (11.4 milliliters) then and handle with the solution of phenol (11.5 grams, 122.2 mmoles) in ether (15 milliliters).This mixture is concentrated in a rotatory evaporator in about 75 ℃.And the oily matter of gained is cooled to 5 ℃.Solid with 5% aqueous acetone solution (20 milliliters) development generates filters, with 5% aqueous acetone solution (30 milliliters) thorough washing throw out.With throw out vacuum-drying, obtain title compound solid (2.2 gram), fusing point 118-120 ℃.
With transparent filtrate evaporate to dryness, (Baker, 60-200 order, 400 milliliters) are with (1: 3 and 1: 1) CH on silicagel column 2Cl 2: hexanes mixtures is a leacheate, with above-mentioned product mixtures chromatographic separation, obtains other title product (total amount is 5.66 grams, 85%)
TLC Rf=0.90(silica gel, CH 2Cl 2: hexane-4: 1)
Press C 13H 10FN 2The cl ultimate analysis,
Calculated value: C, 62.78; H, 4.05; N, 11.27; F, 7.64; Cl, 14.26
Measured value: C, 62.87; H, 3.97; N, 11.34; F, 7.51; Cl, 13.95
MS（M+H） +＝249
C.3-(4-fluorophenyl)-the 5-(1-methylethyl)-1-phenyl-1H-pyrazoles-4-carboxylic acid, ethyl ester
Under nitrogen, drip (2.0 milliliters of ethyl isobutyryls, 12 mmoles) handle alcohol sodium solution (by 0.28 gram, 12 mmole sodium Metal 99.5s and 40 milliliters of dehydrated alcohol preparations), stirring at room 15 minutes, handle with the compound (3.0 grams, 12 mmoles) of B part then.This mixture is used the 10%Hcl(10 milliliter in stirring at room 4.0 hours) reaction is stopped, evaporate to dryness is with ether (3 * 100 milliliters) development gained solid.With the organic extract liquid that salt solution (25 milliliters) washing merges, use anhydrous MgSO 4Drying is filtered evaporate to dryness.On silicagel column with (1: 1) CH 2Cl 2: hexane is a leacheate, with above-mentioned crude product chromatographic separation, obtains light red brown pulpous state title compound (3.27 grams, 77.3%)
TLC:Rf=0.42(silica gel, CH 2Cl 2: hexane-4: 1)
D.3-(4-fluorophenyl)-the 5-(1-methylethyl)-1-phenyl-1H-pyrazoles-4-methyl alcohol
Compound (3.26 grams with the C part, 9.25 mmole) solution in dry ether (22 milliliters) adds lithium aluminum hydride (0.71 gram to, 18.7 cold (0 ℃ in dry ether (32 milliliters) mmole), ice-salt bath) in the suspension, under nitrogen, this mixture was stirred 3.0 hours in 0 ℃.Drip ethyl acetate (5.0 milliliters) and 10%Hcl(11 milliliter successively in 0 ℃) the said mixture reaction is stopped, decant, residuum is developed with ether (2 * 100 milliliters).With the organic extract liquid that salt solution (20 milliliters) washing merges, use anhydrous MgSO 4Drying is filtered, and evaporate to dryness obtains title compound (2.87 grams, 94.4%).
With 100 milligrams of title compounds recrystallization in ether, obtain analytical sample (57 milligrams, fusing point 145-147 ℃).
TLC:Rf=0.17(silica gel, CH 2Cl 2: hexane-4: 1, launch twice)
Ultimate analysis calculated value C 19H 19FN 2O:C, 73.52; H, 6.17; N, 9.03; F, 6.12
Measured value: C, 73.26; H, 6.11; N, 8.96; F, 6.09
MS（M+H） +＝311.
E.3-(4-fluorophenyl)-the 5-(1-methylethyl)-1-phenyl-1H-pyrazoles-4-formaldehyde
Compound (2.59 grams with the D part, 8.34 mmole) solution in dry methylene chloride (22.0 milliliters) adds chloro-chromic acid pyrazoles salt (5.41 grams that stirring rapidly to, 25.1 mmole) in the suspension in dry methylene chloride (32 milliliters), and under nitrogen in stirring at room 4.0 hours.Dilute this reaction mixture with ether (190 milliliters), stirred decant 20 minutes.With ether (100 milliliters) and methylene dichloride (30 milliliters) development tarry residuum, the organic extract liquid that merges is filtered through the silica gel filter bed.With transparent filtrate evaporate to dryness, (Baker, 60-200 order, 300 milliliters) are with (4: 1) CH on silicagel column 2Cl 2: hexane is a leacheate, with the crude product chromatographic separation, obtains title compound (2.40 grams, 93.4%) solid product.
With 100 milligrams of title compounds recrystallization in hexane, obtain analytical sample (50 milligrams, fusing point 103-105 ℃)
TLC:Rf=0.67(silica gel, CH 2Cl 2)
Ultimate analysis calculated value C 19H 17FN 2O:C, 74.01; H, 5.56; N, 9.09; F, 6.16
Measured value: C, 74.18; H, 5.35; N, 9.11; F, 6.12
MS（M+H） +＝309.
F.4-(2,2-dibromo vinyl)-the 3-(4-fluorophenyl)-the 5-(1-methylethyl)-1-phenyl-1H-pyrazoles
(2.296 restrain with E compound partly under argon gas, 7.45 mmole) and triphenyl phosphine (5.86 the gram, 22.1 mmole) mixture in dry methylene chloride (35.0 milliliters) is cooled to-5--10 ℃ (ice-salt bath), in 5 minutes, drip carbon tetrabromide (3.70 grams, 11.0 mmole) solution in dry methylene chloride (12 milliliters) is handled, and stirs 20 minutes in-10 ℃.Reaction mixture rises to room temperature, the saturated NaHCO of impouring 3In (12 milliliters), with methylene dichloride (3 * 60 milliliters) extraction.Use saturated NaHCO 3The organic extract liquid that the washing of (12 milliliters), salt solution (10 milliliters) merges is used anhydrous MgSO 4Drying is filtered evaporate to dryness.
On silicagel column with (1: 1 and 4: 1) CH 2Cl 2: hexanes mixtures is a leacheate, with crude product (11.0 grams, solid) chromatographic separation, obtains title compound (2.96 grams, 96.0% revises productive rate) and unreacted raw material (250.6 milligrams)
With 100 milligrams of title compounds recrystallization in ether-hexane, obtain analytical sample (36.5 milligrams, 93.5 ° of fusing points)
TLC:Rf=0.57(silica gel, CH 2Cl 2: hexane-4: 1)
Ultimate analysis calculated value C 20H 17Br 2FN 2: C, 51.75; H, 3.69; N, 6.04; Br, 34.43; F, 4.09
Measured value: C, 51.78; H, 3.54; N, 6.07; Br, 34.40; F, 3.92
MS（M+H） +＝465
G.4-ethynyl-3-(4-fluorophenyl)-the 5-(1-methylethyl)-1-phenyl-1H-pyrazoles
Compound (2.87 grams with the F part, 6.18 mmole) solution in dry tetrahydrofuran (11.44 milliliters) is cooled to-78 ℃ (dry ice-propanone), under argon gas, drip (11.7 milliliters of 1.6M n-Butyl Lithium/hexanes, 18.6 mmole) handle, stirred 2 hours 20 minutes in-78 ℃ then.Use 25%NH at-78 ℃ 4The cl(16.5 milliliter) makes the reaction mixture stopped reaction, rise to room temperature, with ether (3 * 60 milliliters) extraction.With the organic extract liquid that salt solution (22 milliliters) washing merges, use anhydrous MgSO 4Drying is filtered evaporate to dryness.On silicagel column with (5: 95) ether: hexane is a leacheate, with crude product (1.9 gram) chromatographic separation.Merge required fraction, evaporate to dryness obtains title compound (1.88 grams, 100% productive rate) solid product.
With 100 milligrams of title compounds recrystallization in hexane, obtain analytical sample (63.5 milligrams, fusing point 117-118 ℃)
TLC:Rf=0.37(silica gel, ether: hexane-1: 9)
Ultimate analysis calculated value C 20H 17FN 2: C, 78.92; H, 5.63; F, 6.24; N, 9.21
Measured value: C, 79.12; H, 5.60; F, 6.02; N, 9.12
MS（M+H） +＝305.
H.(S)-and 3-(((1, the 1-dimethyl ethyl) diphenylmethyl silylation) oxygen)-4-(((3-(4-fluorophenyl)-5-(1-methylethyl)-1-phenyl-1H-pyrazoles-4-) ethynyl) the methoxyl group phosphinyl) butyric acid, methyl esters
Handle (S)-3-(((1 with trimethyl silyl diethylamine (2.1 milliliters), the 1-dimethyl ethyl) oxygen diphenylmethyl silylation))-and 4-(hydroxyl methoxyl group phosphinyl) butyric acid, methyl esters (embodiment 1F partly prepares) (2.77 grams, 5.55 the solution in dry methylene chloride (10 milliliters) mmole), and under argon gas in stirring at room 1.0 hours.With the reaction mixture evaporate to dryness, with exsiccant benzene (20 milliliters) azeotropic, vacuum-drying.This syrup is dissolved in the dry methylene chloride (10 milliliters) again, be cooled to-10 ℃ (ice-salt bath), add a DMF, then drip oxalyl chloride (530 μ l) and handle, stirred 15 minutes in-10 ℃, then in stirring at room 1.0 hours.With the mixture evaporate to dryness, with benzene (20 milliliters) azeotropic, vacuum-drying.
Compound (1.12 grams with the G part, 3.67 mmole) be dissolved in dry tetrahydrofuran (9.0 milliliters), be cooled to-78 ℃ (dry ice-propanone baths), under argon gas, use (2.3 milliliters of 1.6M n-Butyl Lithium/hexanes, 3.68 mmole) handle, and stirred 45 minutes in-78 ℃.Above-mentioned phosphonyl chloride is dissolved in dry tetrahydrofuran (6.5 milliliters), is cooled to-78 ℃, drip the acetylene anion solutions by sleeve pipe and handle, whole dropping process two solution all remain on-78 ℃.Reaction mixture was stirred 30 minutes at-78 ℃, drip 25%NH then 4The cl(6.0 milliliter) reaction is stopped, and rise to room temperature.With ether (3 * 100 milliliters) extraction said mixture, use 25%NH 4The cl(10 milliliter) and the organic extract liquid that merges of salt solution (25 milliliters) washing, use anhydrous MgSO 4Drying is filtered evaporate to dryness.
On silicagel column with (1: 9 and 3: 7) acetone: hexanes mixtures is a leacheate, with crude mixture (4.0 gram) chromatographic separation, obtains oily title compound (1.76 grams, 65.2%)
TLC:Rf=0.40(silica gel, hexane: acetone-7: 3)
I.(S)-and 4-((2-(3-(4-fluorophenyl)-5-(1-methylethyl)-1-phenyl-1H-pyrazoles-4-yl) ethynyl) the methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl esters
Use Glacial acetic acid (224 μ l, 3.82 mmoles) and 1.0M(C successively 4H 9) 4NF(3.0 milliliter, 3.0 mmoles) handle the solution of compound (700 milligrams, 0.95 mmole) in dry tetrahydrofuran (9 milliliters) of H part, and under argon gas in stirred overnight at room temperature.Above-mentioned solution is cooled to 0 ℃ of (ice-salt bath) Dropwise 5 %KHSO 4(10 milliliters) are handled, and with ethyl acetate (3 * 75 milliliters) extraction, use 5%KHSO 4(10 milliliters), the organic extract liquid that salt solution (25 milliliters) washing merges filters evaporate to dryness.
Crude product (890 milligrams) is dissolved in the mixture of ether (16 milliliters) and tetrahydrofuran (THF) (12 milliliters), is cooled to 0 ℃ (ice-salt bath), and handle with the excessive diazomethane that is dissolved in the ether.In 0 ℃ with reaction mixture stir about 3 hours, drip Glacial acetic acid and make reaction stop evaporate to dryness.On silicagel column with (1: 1,4: 1 and 9: 1) ethyl acetate: hexanes mixtures is a leacheate, with crude mixture (764 milligrams) chromatographic separation, obtains semi-solid title compound (347 milligrams, 73.2%)
TLC:Rf=0.28(silica gel, ethyl acetate: hexane-4: 1)
Embodiment 43
(S)-and 4-((2-(3-(4-fluorophenyl)-5-(1-methylethyl)-1-phenyl-1H-pyrazoles-4-yl) ethynyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
With 1.0N LiOH(2.4 milliliter, 2.4 mmoles) compound of Processing Example 42 (347 milligrams, the solution in the 0.7 mmole) Zai diox (8.3 milliliters), and under nitrogen, in 55 ℃ (oil baths), stirred 45 minutes.With the reaction mixture evaporate to dryness, and dry in the vacuum.Go up with distilled water (350 milliliters) 50% methanol aqueous solution (250 milliliters) drip washing, with the semi-solid chromatographic separation of gained in Hp-20 chromatographic column (1 " * 3 ").Merge required fraction, evaporate to dryness, vacuum-drying.Above-mentioned product is dissolved in the distilled water, and freeze-drying obtains title compound white ice stem body (338 milligrams, 97.5%)
TLC:Rf=0.50(silica gel, i-prOH: NH 4OH: H 2O-7: 2: 1)
Ultimate analysis calculated value C 24H 22FLi 2N 2O 5P1.95H 2O:C, 55.71; H, 5.04; N, 5.42; F, 3.67; P, 5.99
Measured value: C, 55.90; H, 5.46; N, 5.30; F, 3.95; P, 5.96
H 1-NMR composes (400MHz, CD 3OD):
δ 1.45（d，6H，J＝7）
1.89-2.05（m，2H）
2.38（dd，1H，J＝9，15）
2.52（dd，1H，J＝4，15）
3.06(septet 1H, J=7)
4.48（m，1H）
7.16-8.11（m，9H）
Embodiment 44
(s)-and 4-((2-(3-(4-fluorophenyl)-5-(1-methylethyl)-1-phenyl-1H-pyrazoles-4-yl) ethyl) the methoxyl group phosphino-)-the 3-hydroxybutyric acid, methyl esters
A.(s)-and 3-(((1, the 1-dimethyl ethyl) diphenylmethyl silylation) oxygen)-4-((2-(3-(4-fluorophenyl)-5-(1-methylethyl)-1-phenyl-1H-pyrazoles-4-yl) ethyl) the methoxyl group phosphinyl) butyric acid, methyl esters
Use 10%Pd/C(250mg) solution of compound (1.0 grams, 1.36 mmoles) in dry methyl alcohol (72 milliliters) of Processing Example 42, I part, and in the Pa Er hydrogenator under the pressure of about 40Psi with its hydrogenation.Filter above-mentioned reaction mixture by the diatomite filter bed,, obtain even buttery title compound (1.0 grams, 100% thick productive rate) transparent filtrate evaporate to dryness
TLC: R f=0.27(silica gel, hexane: acetone-7: 3).
B.(s)-and 4-((2-(3-(4-fluorophenyl)-5-(1-methylethyl)-1-phenyl-1H-pyrazoles-4-yl) ethyl) the methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl esters
Use Glacial acetic acid (334 μ l, 5.83 mmoles) and 1.0M(C successively 4H 9) 4NF/THF(4.46 milliliter, 4.46 mmoles) handle the solution of compound (1.05 grams, 1.41 mmoles) in dry tetrahydrofuran (14.0 milliliters) of A part, and under argon gas in stirring at room about 19 hours.With frozen water (28 milliliters) diluted reaction mixture, with ethyl acetate (3 * 100 milliliters) extraction.Use saturated NaHCO 3The organic extract liquid that the washing of (15 milliliters), salt solution (25 milliliters) merges is used anhydrous MgSO 4Drying is filtered evaporate to dryness.(Baker on silicagel column, the 60-200 order, 150 milliliters) with (2: 1,4: 1 and 9: 1) ethyl acetate: hexanes mixtures, ethyl acetate and acetone are leacheate, with crude mixture (1.14 gram) chromatographic separation, obtain semi-solid title compound (623.5 milligrams, 88.0%).
TLC:R f=0.18(silica gel, ethyl acetate: hexane-4: 1)
Embodiment 45
(S)-and 4-((2-(3-(4-fluorophenyl)-5-(1-methylethyl)-1-phenyl-1H-pyrazoles-4-yl) ethyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
Under nitrogen, use 1.0N LiOH(4.28 milliliter, 4.27 mmole) compound of Processing Example 44 is (623.5 milligrams, 1.24 the solution in the mmole) Zai diox (14.7 milliliters) was in 55 ℃ (oil bath) heating 2 hours, in stirring at room about 20 hours then.With the reaction mixture evaporate to dryness, vacuum-drying, and (1 " * 6 ") carry out chromatographic separation (with distilled water (750 milliliters), 10%CH on the HP-20 chromatographic column 3The OH aqueous solution, 20%CH 3The OH aqueous solution (500 milliliters) and 50%CH 3The OH aqueous solution (500 milliliters) drip washing).Merge required fraction, evaporate to dryness obtains required product (560 milligrams, 92.8%).
TLC:R f=0.42(silica gel, i-PrOH: NH 4OH: H 2O-8: 1: 1)
Ultimate analysis calculated value C 24H 26FLi 2N 2O 5P1.16H 2O:(effective molecular weight=507.197): C, 56.83; H, 5.62; N, 5.52; F, 3.74; P, 6.11
Measured value C, 56.83; H, 5.80; N, 5.76; F, 3.46; P, 6.19.
H 1-NMR composes (400MHz, CD 3OD):
δ 1.30（d，6H，J＝7）
1.60-1.78（d，4H）
2.36（m，2H）
2.96-2.99（m，2H）
3.14（m，1H）
4.26（m，1H）
7.14-7.68（m，9H）
Embodiment 46
(S)-and 4-(((4-(4-fluorophenyl)-1-(1-methylethyl)-3-phenyl-1H-pyrazoles-5-yl) ethynyl) the methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl esters
A.2-(4-fluorophenyl)-1-phenyl ethyl ketone
Under argon gas, in 45 minutes, drip 4-fluoro benzyl bromide (5.3 milliliters, 42 mmoles), handle the suspension of magnesium chips (928 milligrams, 38 mmoles) in dry ether (38 milliliters) with the speed that keeps gentle reflux.After dropwising, mixture further refluxed 30 minutes, was cooled to room temperature, with the solution-treated of benzonitrile (2.96 milliliters, 29 mmoles) in dry ether (5 milliliters).With this mixture in stirring at room 4.5 hours, the slowly cold 10%HCl(40 milliliter of impouring) in, extract the suspension of gained with ether (5 * 50 milliliters) and ethyl acetate (2 * 100 milliliters).Use saturated NaHCO 3The organic extract liquid that the washing of (50 milliliters), salt solution (50 milliliters) merges is used anhydrous MgSO 4Drying is filtered evaporate to dryness.
(Baker, 60-200 order, 400 milliliters) are with (1: 4 and 1: 2) CH on silicagel column 2Cl 2: hexanes mixtures is a leacheate, with crude product (9.8 gram) chromatographic separation.Merge required fraction, evaporate to dryness obtains white solid title compound (3.29 grams, fusing point 106-108 ℃).(obtain other 2.60 grams from other fraction that contains the trace starting raw material, overall yield is 94.8%)
TLC:R f=0.60(silica gel, CH 2Cl 2: hexane-1: 1)
Press C 14H 11The FO ultimate analysis,
Calculated value: C, 78.49; H, 5.18; F, 8.87
Measured value: C, 78.22; H, 5.22; F, 9.21
MS（M+H） +＝215
B.2-(4-fluorophenyl)-and 1-phenyl ethyl ketone, (1-methylethyl) track
Handle the A solution of compound (4.45 grams, 21 mmoles) in 95% ethanol (34 milliliters) and Glacial acetic acid (0.74 milliliter) mixture partly with sec.-propyl hydrazine (3.63 milliliters, about 42 mmoles), under nitrogen, heated 1.4 hours in 80 ℃ (oil bath).Also there is some unreacted raw material in thin-layer chromatography (TLC) analysis revealed, thus add sec.-propyl hydrazine (2.0 milliliters, about 23 mmoles) reaction mixture, and further heated 1 hour in 80 ℃ (oil baths).Reaction mixture is cooled to room temperature, in rotatory evaporator, evaporates, remove most of solvent, use methylene dichloride (200 milliliters) dilution then.Wash this organic solvent with salt solution (25 milliliters), use anhydrous MgSO 4Drying is filtered evaporate to dryness.The yellow oil of gained is steamed once in toluene (150 milliliters), obtain being mixed with the title compound crude product (5.63 gram) of two kinds of other components of some initial reactant and trace.
TLC: Rf=0.28(silica gel, CH 2Cl 2: hexane-1: 1)
The preparation method is as follows for the sec.-propyl hydrazine:
In 2.0 hours, under nitrogen, add iodopropane (10.3 milliliters, 0.10 mole) to hydrazine hydrate (48.4 milliliters, 1.0 moles).In 60 ℃ (oil baths) said mixture was stirred 3 hours under nitrogen, cooling is with 20 hours (liquid-liquid extractor) of ether (250 milliliters) extraction.The evaporation ethereal extract obtains sec.-propyl hydrazine (5.63 milliliters, or 5.3 gram).
C. acetic acid, 2-(2-(4-fluorophenyl)-1-phenyl ethylidene)-the 1-(1-methylethyl) hydrazides
(5.63 restrain with B crude product partly under nitrogen, about 21 mmoles) and (5.85 milliliters of triethylamines, 42 mmoles) mixture in dry toluene (210 milliliters) is cooled to 0 ℃ (ice-salt bath), and handles with Acetyl Chloride 98Min. (1.86 milliliters, 26.3 mmoles).Reaction mixture under agitation rises to room temperature (in 1.5 hours) gradually, with ether (700 milliliters) dilution, filters.Use anhydrous Na 2SO 4Dry transparent clarifying filtrate is filtered, evaporate to dryness, and in toluene (300 milliliters), steam once.(Baker, 60-200 order, 400 milliliters) use (1: 1 and 2: 1) CH on silicagel column 2Cl: hexanes mixtures, CH 2Cl 2(9: 1) CH 2Cl: CH 3OH drip washing, semisolid (7.1 gram) chromatographic separation with being obtained obtains title compound crude product (4.11 gram).On another silicagel column (with (4: 1) ethyl acetate: hexane drip washing) with this crude product chromatographic separation once more.Merge required fraction, evaporate to dryness obtains yellow thickness buttery title compound (3.89 gram).
TLC:Rf=0.47(silica gel, ethyl acetate: hexane-1: 1).
D.4-(4-fluorophenyl)-5-methyl isophthalic acid-(1-methylethyl)-3-phenyl-1H-pyrazoles
Handle the solution of compound (1.50 grams, 4.80 mmoles) in two (2-methoxy ethyl) ether (48 milliliters) of C part with solid potassium hydroxide (615 milligrams, 10.96 mmoles), and under nitrogen, heated 2.0 hours in 80 ℃ (oil bath).Handle this reaction mixture with second batch of potassium hydroxide (700 milligrams, 12.5 mmoles), in 80 ℃ of heating 2 hours, then in stirring at room 16 hours.This mixture is poured in the water (300 milliliters), used the extraction of ether (3 * 150 milliliters) and ethyl acetate (200 milliliters) successively.Merge organic solution, with 3% cold HCl(500 milliliter), salt solution (2 * 100 milliliters) washs, and uses anhydrous MgSO 4Drying is filtered evaporate to dryness.(Baker, 60-200 order, 500 milliliters) are with (1: 4) ethyl acetate on silicagel column: hexane is a leacheate, with crude product (3.5 gram) chromatographic separation, obtains cream-colored solid title compound (1.33 grams, 94.3%), fusing point 135-137 ℃.TLC:Rf=0.63(silica gel, ethyl acetate: hexane-1: 4).
E.4-(4-fluorophenyl)-the 1-(1-methylethyl)-3-phenyl-1H-pyrazoles-5-formaldehyde
Under nitrogen with CuSO 45H 2O(2.21 gram, 8.85 mmoles) and the mixture heating up to 65 ℃ (oil bath) of Potassium Persulphate (9.53 grams, 35.3 mmoles) in acetonitrile (65 milliliters) and water (39 milliliters), and with compound (2.6 the restrain 8.83 mmoles) processing of D part.To bathe temperature and rise to 75 ℃ lentamente.In 75 ℃ of maintenances 40 minutes, use water-bath to be cooled to room temperature then.With methylene dichloride (45 milliliters) diluted reaction mixture, stirred 10 minutes, decant, other gets methylene dichloride (3 * 45 milliliters) and extracts this aqeous suspension.With the organic extract liquid that salt solution (2 * 30 milliliters) washing merges, use anhydrous MgSO 4Drying is filtered evaporate to dryness.(LPS-1) is with (1: 9) ethyl acetate on silicagel column: hexane is a leacheate, with crude product (2.75 gram) chromatographic separation, obtains solid title compound (1.57 grams, 57.7%).
TLC: Rf=0.72(silica gel, ethyl acetate: hexane-1: 4).
F.5-(2,2-dibromo vinyl)-the 4-(4-fluorophenyl)-the 1-(1-methylethyl)-3-phenyl-1H-pyrazoles
(1.75 restrain with E compound partly under argon gas, 5.68 mmole) and triphenyl phosphine (4.6 the gram, 16.8 mmole) mixture in dry methylene chloride (27.0 milliliters) is cooled to-5 ℃--10 ℃ (ice-salt bath), in 5 minutes, drip carbon tetrabromide (2.82 grams, 8.42 mmole) solution in dry methylene chloride (9 milliliters) is handled, and stirs 20 minutes in-10 ℃.The temperature of reaction mixture rises to room temperature, pours saturated NaHCO into 3In (9.0 milliliters), with methylene dichloride (3 * 50 milliliters) extraction.Use saturated NaHCO 3The organic extract liquid that the washing of (10 milliliters), salt solution (10 milliliters) merges is used anhydrous MgSO 4Drying is filtered evaporate to dryness.
On silicagel column with (1: 0,1: 4) CH 2Cl 2: hexanes mixtures is a leacheate, with the crude product chromatographic separation.Merge required fraction, obtain oily title compound (2.35 grams, 91.4%).
TLC: R f=0.32(silica gel, CH 2Cl 2: hexane-1: 1).
G.5-ethynyl-4-(4-fluorophenyl)-the 1-(1-methylethyl)-3-phenyl-1H-pyrazoles
Compound (1.89 grams with the F part, 4.08 mmole) solution in dry tetrahydrofuran (7.6 milliliters) is cooled to-78 ℃ (dry ice-propanone), under argon gas, drip (5.2 milliliters of 1.6M butyllithium/hexanes, 8.18 mmole, 2 equivalents) handle, and stirred 1 hour 20 minutes in-78 ℃.Use 25%NH at-78 ℃ 4The Cl(11.0 milliliter) termination reaction rises to room temperature, with methylene dichloride (3 * 50 milliliters) extraction.With the organic extract liquid that salt solution (15 milliliters) washing merges, use anhydrous MgSO 4Drying is filtered evaporate to dryness.On silicagel column with (1: 4; 1: 1) CH 2Cl 2: hexanes mixtures is a leacheate, with crude product (1.77 gram) chromatographic separation, obtains title compound (648 milligrams) and contains title compound and the mixing fraction of the compound of F part.This is mixed fraction and mixes from the product of another operation (490 milligrams derive from the compound of 1.1 mmole F part), and on second chromatographic column (with (1: 9) CH 2Cl 2: hexane drip washing) carry out chromatographic separation.Merge required fraction, evaporate to dryness obtains oily title compound (1.02 grams carry out productive rate to the starting raw material that reclaims and proofread and correct, and productive rate is 71.5%).
H.(S)-and 3-(((1, the 1-dimethyl ethyl) diphenylmethyl silylation) oxygen)-4-(((4-(4-fluorophenyl)-1-(1-methylethyl)-3-phenyl-1H-pyrazoles-5-yl) ethynyl) the methoxyl group phosphinyl) butyric acid, methyl esters
Under argon gas, stirred 1 hour in the phosphonic acids mono-methyl (2.341 grams, 5.01 mmoles) and the body lotion of trimethyl silyl ethamine (1.90 milliliters, 10 mmoles) in dry methylene chloride (9.5 milliliters) of room temperature with embodiment 1F part.With this mixture evaporate to dryness, with exsiccant benzene (15 milliliters) azeotropic, vacuum-drying.The thickness oily matter that generates is dissolved in dry methylene chloride (9.5 milliliters) again, handles, be cooled to-10-0 ℃ (ice-salt bath), and dropping oxalyl chloride (480 μ l, 5.47 mmoles) is handled with a DMF.Can be observed violent gas evolution, in-10-0 ℃ with this dark yellow solution stirring 15 minutes, then in stirring at room 1 hour.With the reaction mixture evaporate to dryness, with benzene (18 milliliters) azeotropic, vacuum-drying.
(1.016 restrain with G compound partly under argon gas, 3.34 mmole) solution in dry tetrahydrofuran (8 milliliters) is cooled to-78 ℃ (dry ice-propanone), handle with 1.6M n-Butyl Lithium/hexane (2.1 milliliters, 3.36 mmoles), and stirred 1.0 hours in-78 ℃.Above-mentioned phosphonyl chloride is dissolved in the dry tetrahydrofuran (8 milliliters), is cooled to-78 ℃ (dry ice-propanone) under argon gas, drip the acetylene anion solutions by sleeve pipe and handle, above-mentioned two solution all remain on-78 ℃ in whole dropping process.In-78 ℃ reaction mixture was stirred 1.0 hours, drip 25%NH 4The Cl(9 milliliter) termination reaction rises to room temperature then.With ether (3 * 100 milliliters) extraction said mixture, use 25%NH 4The Cl(10 milliliter), the organic extract liquid that merges of salt solution (25 milliliters) washing, use anhydrous MgSO 4Drying is filtered evaporate to dryness.
On silicagel column with (1: 9 and 1: 4) acetone: hexanes mixtures is a leacheate, with the crude product chromatographic separation, obtains oily title compound (1.59 gram, 64.8%).TLC: Rf=0.43(silica gel, acetone: hexane-3: 7)
I, (S)-4-(((4-(4-fluorophenyl)-1-(1-methylethyl)-3-phenyl-1H-pyrazoles-5-yl) ethynyl) methoxyl group phosphinyl)-and the 3-hydroxybutyric acid, methyl esters
Use Glacial acetic acid (320 μ l, 5.46 mmoles) and 1M(C successively 4H 9) 4NF(4.26 milliliter, 4.26 mmoles) handle the solution of compound (1.0 grams, 1.36 mmoles) in dry tetrahydrofuran (13 milliliters) of H part, and under argon gas in stirred overnight at room temperature.Reaction mixture is cooled to 0 ℃ (ice-salt bath), uses 5%KHSO 4(15 milliliters) are handled, with ethyl acetate (3 * 125 milliliters) extraction.Use 5%KHSO 4The organic extract liquid that the washing of (2 * 25 milliliters), salt solution (25 milliliters) merges is used anhydrous MgSO 4Drying is filtered evaporate to dryness.
Crude product (1.06 gram) is dissolved in the mixture of ether (23 milliliters) and tetrahydrofuran (THF) (18 milliliters), is cooled to 0 ℃ (ice-salt bath), the excessive diazomethane that is used in the ether is handled, and stirs 4 hours in 0 ℃.Dripping Glacial acetic acid makes reaction stop evaporate to dryness, vacuum-drying.On silicagel column with (1: 2) acetone: hexane is a leacheate, with the crude product chromatographic separation, merges required fraction, and evaporate to dryness obtains oily title compound (330 milligrams, 4.87%).
TLC: Rf=0.23(silica gel, ethyl acetate: hexane-4: 1)
Embodiment 47
(S)-and 4-(((4-(4-fluorophenyl)-1-(1-methylethyl)-3-phenyl-1H-pyrazoles-5-yl) ethynyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
With 1N LioH(2.29 milliliter, 2.29 mmole) compound of Processing Example 46 is (330 milligrams, 0.66 the solution in the mmole) Zai diox (7.8 milliliters), and stirring 1.5 hours in 55 ℃ (oil bath) under argon gas is then in stirring at room 16 hours.With reaction mixture evaporate to dryness, vacuum-drying.(1 " * 10 ") use distilled water (750 milliliters), 10%CH on the HP-20 chromatographic column 3The OH aqueous solution (500 milliliters), 20%CH 3The oH aqueous solution (500 milliliters) and 50%CH 3The oH aqueous solution (500 milliliters) drip washing is with the crude product chromatographic separation.Merge required fraction, evaporate to dryness, vacuum-drying.Solid product is dissolved in the distilled water, and freeze-drying obtains the fluffy solid-state freeze-drying body of compound (275 milligrams, 99.5%).
TLC:Rf=0.57(silica gel, i-ProH: NH 4OH: H 2O-8: 1: 1), C 24H 22FLi 2N 2O 5P2.28H 2O(effective molecular weight=523.310) ultimate analysis.
Calculated value: C, 55.08; H, 5.11; N, 5.35; F, 3.63; P, 5.92
Observed value: C, 55.08; H, 4.98; N, 5.47; F, 3.66; P, 5.99
Ultimate analysis calculated value C 24H 22FLi 2N 2O 5P2.28(effective molecular weight=523.310): C, 55.08; H, 5.11; N, 5.35; F, 3.63; P, 5.92
Measured value C, 55.08; H, 4.98; N, 5.47; F, 3.66; P, 5.99
IR（KBr）：2172cm -1（C≡C）
H 1-NMR composes (400MHz, CD 3OD):
δ 1.57（d，6H，J＝7Hz）
1.86-2.01（m，2H）
2.37（dd，1H，J＝8）
2.50（dd，1H，J＝4）
4.40（m，1H）
5.01(septet 1H, J=7)
7.04-7.39（m，9H）
Embodiment 48
(S)-and 4-((2-(4-(4-fluorophenyl)-1-(1-methylethyl)-3-phenyl-1H-pyrazoles-5-yl) ethyl) the methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl esters
A, (S)-3-(((1, the 1-dimethyl ethyl) diphenylmethyl silylation) oxygen)-4-((2-(4-(4-fluorophenyl)-1-(1-methylethyl)-3-phenyl-1H-pyrazoles-5-yl) ethyl) butyric acid methoxyl group phosphinyl), methyl esters
Use the 10%Pd/C(155 milligram) solution of compound (608 milligrams, 0.85 mmole) in dry methyl alcohol (63 milliliters) of Processing Example 46H part, and spend the night in room temperature pressure hydrogenation with about 40PSi in the Pa Er hydrogenator.Dilute this suspension with methyl alcohol (50 milliliters), and filter, with this filter bed of methyl alcohol thorough washing by the diatomite filter bed in the millipore filter.With clarifying filtrate evaporate to dryness, vacuum-drying obtains even buttery title compound (559 milligrams, 90.9%), its H 1-NMR and C 13-NMR spectrum data are coincide.
RC: Rf=0.20(silica gel, acetone: hexane-3: 7, UV)
B, (S)-4-((2-(4-fluorophenyl)-1-(1-methylethyl)-3-phenyl-1H-pyrazoles-5-yl) ethyl) methoxyl group phosphinyl)-and the 3-hydroxybutyric acid, methyl esters
Under nitrogen, use Glacial acetic acid (176 μ l, 3.0 mmoles, 4 equivalents) and 1.0M(C successively 4H 9) 4NF/ hexane (2.34 milliliters, 2.34 mmoles, 3.1 equivalents) is handled the solution of compound (559 milligrams, 0.75 mmole) in dry tetrahydrofuran (7.5 milliliters) of A part, and in stirring at room about 20 hours.Dilute this reaction mixture with frozen water (20 milliliters),, use saturated NaHCO with ethyl acetate (3 * 70 milliliters) extraction 3The organic extract liquid that the washing of (10 milliliters), salt solution (20 milliliters) merges is used anhydrous MgSO 4Drying is filtered evaporate to dryness.On silicagel column, use (1: 4) ethyl acetate: hexane, ethyl acetate and (4: 1) acetone: hexane drip washing, with crude product (580 milligrams) chromatographic separation.Merge required fraction, evaporate to dryness, vacuum-drying obtains even buttery title compound (337 milligrams, 89.4%) TLC: Rf=0.18(silica gel, acetone: hexane-1: 1, UV)
Embodiment 49
(S)-and 4-((2-(4-(4-fluorophenyl)-1-(1-methylethyl)-3-phenyl-1H-pyrazoles-5-yl) ethyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
Under argon gas with 1.0N LioH(2.32 milliliter, 3.5 equivalents) (337.0 milligrams, the solution in the 0.67 mmole) Zai diox (8.0 milliliters) stirred 3.0 hours in 55 ℃ (oil bath), then in stirring at room 20 hours for the compound of Processing Example 48.With the reaction mixture evaporate to dryness, and dry 1.0 hours of vacuum (pump).(1 " * 8 ") use distilled water (500 milliliters), 10%CH on the HP-20 chromatographic column 3The oH aqueous solution (500 milliliters), 20%CH 3The oH aqueous solution (500 milliliters) and 50%CH 3The drip washing of the oH aqueous solution is with the crude product chromatographic separation.Merge required fraction, evaporate to dryness, vacuum-drying.The solid of gained is dissolved in the distilled water, freezes also freeze-drying and spend the night, obtain title compound white fluffy freeze-drying body (280.4 milligrams, 82.4%), ultimate analysis, mass spectrum, IR and H 1-NMR spectrum data are coincide.
TLC: Rf=0.45(silica gel, i-ProH: NH 4OH: H 2O-8: 1: 1, UV)
Obtain 24 milligrams of not too pure products in addition from other fraction.
Ultimate analysis calculated value C 24H 26FLi 2N 2O 5P1.19H 2The O(effective molecular weight)=and 507.733:C, 56.77; H, 5.63; N, 5.51; F, 3.74; P, 6.10
Measured value C, 52.77; H, 5.69; N, 5.49; F, 3.91; P, 6.50
IR（KBr）#69377（1589CM -1，C＝O of COO -）
H 1-NMR composes (400MHz, CD 3OD):
δ 1.55（d，6H，J＝7，H j）
1.64-1.84（m，4H，-，H c+H d）
2.34（m，2H，-，H a）
2.91（pseudo quartet，2H，-，H e）
4.25（m，1H，-，H 6）
4.77(septet, 1H, part is covered in the HOD signal)
HOD signal），-，H i）
7.05-7.32(m, 9H, aromatic hydrocarbons proton)
Embodiment 50
(S)-and 4-(((1-(4-fluorophenyl)-4-(1-methylethyl)-2-phenyl-1H-imidazoles-5-yl) ethynyl) the methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl esters
A, N-benzoyl propylhomoserin
(20 restrain with Xie Ansuan under nitrogen, 0.17 the mole) at tetrahydrofuran (THF) (20 milliliters) and 2N NaoH(111 milliliter) in solution be cooled to 10 ℃ (ice-water-baths), drip (23.8 milliliters of Benzoyl chlorides, 0.21 mole) handle, the temperature of this reaction mixture is risen to room temperature, stirred 3.0 hours, and be cooled to 0 ℃ (ice-salt bath) then, and handle with the vitriol oil (8.0 milliliters).With ethyl acetate (3 * 200 milliliters) extraction said mixture.The organic extract liquid that water (100 milliliters), salt solution (50 milliliters) washing merge is used anhydrous MgSO 4Drying is filtered, and evaporate to dryness obtains solid title compound (41.97 grams, 100% thick productive rate)
(260 milligrams) product recrystallization in ethyl acetate and sherwood oil obtains title compound analytical sample (205 milligrams, fusing point 132-133 ℃) on a small quantity
TLC: Rf=0.10(silica gel, acetone: hexane-1: 1)
Ultimate analysis calculated value: C, 65.14; H, 6.83; N, 6.33
Measured value: C, 64.81; H, 6.79; N, 6.29
MS（M+H） +＝222
B, N-(1-ethanoyl-2-methyl-propyl) benzamide
With two parts of 4-Dimethylamino pyridines (2.07 grams, 0.017 mole) handle compound (41.7 grams of A part, about 0.17 mole) and the mixture of triethylamine (47.3 milliliters, 0.34 mole) in acetic anhydride (48 milliliters), under nitrogen in stirring at room 16 hours.Reaction mixture is cooled to 0 ℃ (ice-salt bath), uses the methyl alcohol termination reaction, and stirred 30 minutes.The light brown precipitation that generates is leached, water (1(11 liter) thorough washing, and be dissolved in again in the methylene dichloride (750 milliliters).Use anhydrous MgSO 4The solution of dry gained filters, and evaporate to dryness obtains crude product (35.9 gram)
This crude product is dissolved in ether (1.3 liters), and the filtering insoluble solid is concentrated into about 300 milliliters volume with clarifying filtrate, and cools off in ice bath.Leach the title compound (21.35 grams, fusing point 88-90 ℃) of cream-colored precipitation forms.(BaKer, 60-200 order, 600 milliliters) are with (1: 7 and 1: 4) ethyl acetate on silicagel column: hexanes mixtures is a leacheate, will purify by the solid that evaporated filtrate obtains, and obtains other 4.77 gram title compounds.With a small amount of title compound recrystallization in ether, fusing point 88-89 ℃.
TLC: Rf=0.75(silica gel, acetone: hexane-1: 1)
Ultimate analysis calculated value: C, 70.20; H, 7.81; N, 6.39
Measured value: C, 70.79; H, 7.68; N, 6.31
MS（M+H） +＝220
C, N-(1-(1-((4-fluorophenyl) imino-) ethyl)-2-methyl-propyl) benzamide
With (12 milliliters of 4-fluoroanilines, 0.127 mole, 1.11 equivalent) and hydration tosic acid (125 milligrams) treatments B part of compounds (25.0 the gram, 0.114 solution in dry toluene (250 milliliters) mole), under nitrogen with Dean-Starke distillation receptor with this reaction mixture refluxed 20 hours.Pale red brown solution is cooled to-10 ℃ (ice-salt bath), is used for next step like this and synthesizes.
D, 1-(4-fluorophenyl)-5-methyl-4-(1-methylethyl)-2-phenyl-1H-imidazoles
Be used for the cold soln that dry methylene chloride (200 milliliters) is diluted C part of compounds (about 0.114 mole) in-10 ℃ (ice-salt baths), add phosphorus pentachloride (47.5 grams, 0.228 mole) in batches and handle.The cream-colored slurries that obtain are heated up,, are cooled to room temperature, slowly impouring ice (400 gram) and 50%NaoH(105 milliliter in refluxed under nitrogen 2.5 hours) mixture in.Separate organic phase, with methylene dichloride (2 * 200 milliliters) aqueous phase extracted.With the organic extract liquid that salt solution (2 * 100 milliliters) washing merges, use anhydrous MgSO 4Drying is filtered evaporate to dryness.
(Baker, 60-200 order, 600 milliliters) were with (1: 9 on silicagel column, 1: 4) ethyl acetate: hexanes mixtures is a leacheate, and crude mixture (35.0 gram) is purified, and obtains white needles title compound (29.24 grams, fusing point 146-148 ℃, 87%)
TLC: Rf=0.40(silica gel, ethyl acetate: hexane-1: 4)
Ultimate analysis calculated value: C, 77.52; H, 6.51; N, 9.52; F, 6.45
Measured value: C, 77.48; H, 6.69; N, 9.40; F, 6.45
MS（M+H） +＝295
E.1-(4-fluorophenyl)-the 4-(1-methylethyl)-2-phenyl-1H-imidazoles-5-formaldehyde
(8.50 restrain with the hydration blue vitriol under nitrogen, 34.0 mmole) and Potassium Persulphate (36.8 the gram, 0.136 the mixture heating up to 65 ℃ (oil bath) in acetonitrile (250 milliliters) and water (150 milliliters) mixed solvent mole), compound (10 grams, 34.0 mmoles) with the D part is handled.This reaction mixture slowly is heated to 75 ℃,, is cooled to room temperature then in 75 ℃ of maintenances 40 minutes.With this solution decant, with the solids constituent that generates from, with methylene dichloride (3 * 200 milliliters) aqueous phase extracted and solid mutually,, use anhydrous MgSO with the organic extract liquid that salt solution (2 * 100 milliliters) washing merges 4Drying is filtered evaporate to dryness.(Baker, 60-200 order, 600 milliliters) are with (5: 95,1: 7) ethyl acetate on silicagel column: hexanes mixtures is a leacheate, with crude product (17.0 gram) chromatographic separation, obtains solid title compound (6.27 grams, 59.8%).
With 200 milligrams of title compounds at ether: recrystallization in the hexane obtains analytical sample (76 milligrams, fusing point 160-161 ℃).
TLC: R f=0.34(silica gel, ethyl acetate: hexane-1: 4).
Ultimate analysis calculated value C, 74.01; H, 5.56; N, 9.09; F, 6.16
Measured value C, 73.98; H, 5.68; N, 9.04; F, 6.09
MS（M+H） +＝309
F.5-(2,2-dibromo vinyl)-the 1-(4-fluorophenyl)-the 4-(1-methylethyl)-2-phenyl-1H-imidazoles
(1.75 restrain with E compound partly under argon gas, 5.68 mmole) and triphenyl phosphine (4.46 the gram, 16.8 mmole) solution in dry methylene chloride (27.0 milliliters) is cooled to-5--10 ℃ (ice-salt bath), dripping the solution of carbon tetrabromide (2.82 grams, 8.42 mmoles) in dry methylene chloride (9 milliliters) in 5 minutes handles.This mixture in-10 ℃ of stirrings 20 minutes, in the impouring saturated sodium bicarbonate (9.0 milliliters), is extracted with methylene dichloride (3 * 50 milliliters) then.Use saturated NaHCO 3The organic extract liquid that the washing of (10 milliliters), salt solution (10 milliliters) merges is used anhydrous MgSO 4Drying is filtered evaporate to dryness.On silicagel column with (1: 7,1: 4) CH 2Cl 2: hexanes mixtures is a leacheate, with crude product (8.07 gram) chromatographic separation, obtains solid title compound (2.35 grams, 91.4%).
With the compound of 100 milligrams of F part at ether: recrystallization in the hexane obtains analytical sample (49 milligrams, fusing point 164-165 ℃).
TLC: R f=0.32(silica gel, CH 2Cl 2: hexane-1: 1)
Ultimate analysis calculated value C, 51.75; H, 3.69:N, 6.04; F, 4.09; Br, 34.43
Measured value C, 51.80; H, 3.71; N, 6.02; F, 4.08;
Br，34.25
MS（M+H） +＝465.
G.5-ethynyl-1-(4-fluorophenyl)-the 4-(1-methylethyl)-2-phenyl-1H-imidazoles
The solution of compound (3.065 grams, 6.60 mmoles) in dry tetrahydrofuran (12.5 milliliters) of F part is cooled to-78 ℃ (dry ice-propanone), under argon gas, handles with 1.6M n-Butyl Lithium/hexane (8.4 milliliters, 13.4 mmoles).This reaction mixture was stirred dropping 25%NH 1 hour 20 minutes in-78 ℃ 4The Cl(18 milliliter) termination reaction rises to room temperature, with ether (3 * 100 milliliters) extraction.With the organic extract liquid that salt solution (25 milliliters) washing merges, use anhydrous MgSO 4Drying is filtered evaporate to dryness.(Baker, 60-200 order, 400 milliliters) are with (1: 9,1: 4) ethyl acetate on silicagel column: hexanes mixtures is a leacheate, with crude product (2.08 gram) chromatographic separation, obtains solid title compound (1.97 grams, 97.8%).
Compound recrystallization in hexane with 92 milligrams of G parts obtains analytical sample (59 milligrams, fusing point 148-150 ℃)
TLC:Rf=0.60(silica gel, ethyl acetate: hexane-1: 4)
Ultimate analysis calculated value: C, 78.92; H, 5.63; N, 9.21; F, 6.24
Measured value: C, 78.95; H, 5.83; N, 9.07; F, 6.63
MS（M-H） -＝303.
H.(S)-and 3-(((1, the 1-dimethyl ethyl) diphenylmethyl silylation) oxygen)-4-(((1-(4-fluorophenyl)-4-(1-methylethyl)-2-phenyl-1H-imidazoles-5-yl) ethynyl) the methoxyl group phosphinyl) butyric acid, methyl esters
At room temperature, thick phosphonic acids mono-methyl (3.54 grams, 7.86 mmoles) and the mixture of trimethyl silyl diethylamide (2.70 milliliters, 14.21 mmoles) in anhydrous methylene chloride with embodiment 1F part stirred in argon gas 1.0 hours.This mixture is evaporated to dried, with dry-out benzene (26 milliliters) azeotropic and vacuum-drying.This viscous oil is dissolved in the anhydrous methylene chloride (14 milliliters) again, handles with 2 DMF, is cooled to-10 ℃ (ice-salt bath) and drips processing with oxalyl chloride (0.68 milliliter, 7.79 mmoles).Observe gas and acutely emit, then this brown solution was stirred 15 minutes down at-10 ℃, at room temperature stirred then 1.0 hours.This reaction mixture is evaporated to dried, with dry-out benzene (26 milliliters) azeotropic and vacuum-drying.
Compound (1.43 grams with the G part, 4.7 the solution in anhydrous tetrahydro furan (11.5 milliliters) mmole), in argon gas, be cooled to-78 ℃ (dry ice/acetone), and with (2.94 milliliters of 1.6M n-Butyl Lithium/hexanes, 4.7 mmole) handle, stirred 30 minutes down at-78 ℃ then.Top phosphonyl chloride is dissolved in the anhydrous tetrahydro furan (11.5 milliliters), is cooled to-78 ℃ (dry ice-propanone) in argon gas, and drip processing with the anionic solution of acetylene by sleeve pipe, two solution all remain on-78 ℃ in whole reinforced process.This reaction mixture stirred 30 minutes down at-78 ℃, by dripping 25%NH 4The Cl(13 milliliter) stopped reaction makes its heat to room temperature, uses extracted with diethyl ether (3 * 130 milliliters) then.The organic extract liquid 25%NH that merges 4The Cl(15 milliliter), salt solution (30 milliliters) washs dry (anhydrous MgSO 4), filter and be evaporated to dried.
This crude product mixture (4.3 gram) carries out chromatography, this post acetone: hexanes mixtures (5: 95 on silicagel column; 1: 4) wash-out.Merge desired fraction, be evaporated to driedly, obtain the title compound (2.18 gram, 62.9%) of light brown pulpous state
TLC: Rf0.13(silica gel; Hexane: acetone-7: 3).
I.(S)-and 4-(((1-(4-fluorophenyl)-4-(1-methylethyl)-2-phenyl-1H-imidazoles-5-yl) ethynyl) the methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl esters
In argon gas, the solution of compound (974 milligrams, 1.32 mmoles) in anhydrous tetrahydro furan (13.0 milliliters) of H part is used Glacial acetic acid (310 microlitres, 5.29 mmoles) and 1M(C continuously 4H 9) 4The NF(4.14 milliliter, 4.14 mmoles) handle, and at room temperature stir and spend the night.This reaction mixture is cooled to 0 ℃ (ice-water bath), uses 5%KHSO 4(14 milliliters) are handled, and use ethyl acetate (3 * 125 milliliters) extraction then.The organic extract liquid 5%KHSO that merges 4The washing of (16 milliliters), salt solution (35 milliliters), dry (anhydrous MgSO 4), filter and be evaporated to dried.
This thick product (1.48 gram) is dissolved in the mixture of ether (22 milliliters) and anhydrous tetrahydro furan (17 milliliters), is cooled to 0 ℃ (ice-water bath), handle, stirred 4.0 hours down at 0 ℃ then with the excessive diazomethane that is dissolved in ether.This reaction mixture is evaporated to dry doubling vacuum-drying by dripping the Glacial acetic acid stopped reaction.This thick product chromatography on silicagel column, this post EtOAC: hexanes mixtures (1: 1; 4: 1) wash-out.Merge desired fraction and obtain solid title compound (304 milligrams, 46.2%).
TLC: Rf0.33(silica gel; EtOAC: hexane-4: 1)
Embodiment 51
(S)-and 4-(((1-(4-fluorophenyl)-4-(1-methylethyl)-2-phenyl-1H-imidazoles-5-yl) ethynyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
With (304 milligrams of the compounds of embodiment 50,0.6 the solution of mmole) Yu diox (7.1 milliliters) 1N LiOH(2.03 milliliter, 2.08 mmole) handle, under 55 ℃ (oil bath) in argon gas, stirred 1.5 hours, at room temperature stirred then 24 hours.This reaction mixture is evaporated to dry doubling vacuum-drying.This thick product is gone up chromatography at HP-20 post (1 " * 7 "), this post distilled water (750 milliliters), 10%CH 3The OH aqueous solution (500 milliliters), 20%CH 3The OH aqueous solution (500 milliliters) and 50%CH 3The OH aqueous solution (500 milliliters) wash-out.Merge desired fraction, be evaporated to dry doubling vacuum-drying.Be dissolved in the distilled water this solid product and lyophilize, obtain title compound, be loose solid lyophilize thing (257 milligrams, 84.1%).
Other fraction: TLC:R f0.38(silica gel
i-PrOH∶NH 4OH∶H 2O-8∶1∶1）.
Ultimate analysis calculated value: C 24H 22FLi 2N 2O 5P1.52H 2O:C, 56.56; H, 4.95; N, 5.49; F, 3.73; P, 6.08
Measured value: C, 56.56; H, 4.94; N, 5.32; F, 3.89; P, 5.99.
H 1-NMR composes (400MHz, CD 3OD):
δ 1.37（d，6H，J＝7Hz）
1.79（m，2H）
2.31（dd，1H，J＝9.15Hz）
2.43（dd，1H，J＝4.15Hz）
3.24(septet, 1H, J=7Hz)
4.26（m，1H）
7.17-7.35（m，9H）.
IR（KBr）2163（C≡C），1590（C＝O）cm -1.
Embodiment 52
(S)-and 4-((2-(1-(4-fluorophenyl)-4-(1-methylethyl)-2-phenyl-1H-imidazoles-5-yl) ethyl) the methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl esters
A.(S)-and 3-(((1, the 1-dimethyl ethyl) diphenylmethyl silylation) oxygen)-4-((2-(1-(4-fluorophenyl)-4-(1-methylethyl)-2-phenyl-1H-imidazoles-5-yl) ethyl) the methoxyl group phosphinyl) butyric acid, methyl esters
The solution 10%pd/c(213 milligram of compound (839 milligrams, 1.14 mmoles) in anhydrous methanol (86 milliliters) with embodiment 50H part) processing, and under～40psi, in the Pa Er hydrogenator, spend the night in room temperature hydrogenation.This suspension filters by the diatomite filter bed, and clear filtrate is evaporated to dry doubling vacuum-drying, obtains the title compound (853 milligrams, productive rate 100%) of thick pulpous state.
TLC:R f0.17(silica gel; Hexane: acetone-7: 3).
B.(S)-and 4-((2-(1-(4-fluorophenyl)-4-(1-methylethyl)-2-phenyl-1H-imidazoles-5-yl) ethyl) the methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl esters
The solution of compound (853 milligrams ,～1.14 mmoles) in anhydrous tetrahydro furan (10.0 milliliters) of A part is used Glacial acetic acid (270 microlitres, 4.60 mmoles) and 1.0M(C continuously 4H 9) 4NF/ hexane (3.62 milliliters, 3.62 mmoles) is handled, and at room temperature stirs in argon gas then and spends the night.This reaction mixture is with frozen water (25 milliliters) dilution and with ethyl acetate extraction (3 * 100 milliliters).The saturated NaHCO of organic extract liquid that merges 3The washing of (15 milliliters), salt solution (25 milliliters), dry (anhydrous MgSO 4), filter and be evaporated to dried.
This crude product (958 milligrams) chromatography on silicagel column, this post acetone: hexanes mixtures wash-out (1: 1,4: 1).Merge desired fraction, be evaporated to dry doubling vacuum-drying, obtain solid title compound (443 milligrams, 77.0%).
TLC:R f0.13(silica gel; Acetone: hexane-1: 1).
Embodiment 53
(S)-and 4-((2-(1-(4-fluorophenyl)-4-(1-methylethyl)-2-phenyl-1H-imidazoles-5-yl) ethyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
With (443 milligrams of the compounds of embodiment 52,0.88 the 1.0N LiOH(3.05 milliliter of the solution in the mmole) Yu diox (10.5 milliliters), 3.09 mmole) handle, and under 55 ℃ (oil baths), in argon gas, stirred 3.0 hours, at room temperature stirred～20 hours then.This reaction mixture is evaporated to dry doubling vacuum-drying.Crude product carries out chromatography on HP-20 post (1 " * 8 "), this post distilled water (750 milliliters), 10%CH 3The OH aqueous solution (500 milliliters), 20%CH 3The OH aqueous solution (500 milliliters) and 50%CH 3OH aqueous solution wash-out.Merge desired fraction and be evaporated to dried.The gained solid is dissolved in the distilled water (30 milliliters), and lyophilize obtains title compound then, is loose white solid (376.4 milligrams, 83.9%).
TLC:R f=0.40(silica gel; I-PrOH: NH 4OH: H 2O-8: 1: 1)
Ultimate analysis calculated value: C 24H 26FLiH 2N 2O 5P0.84H 2O(effective molecular weight=501.46): C, 57.43; H, 5.76; N, 5.69; F, 3.99; P, 6.08
Measured value: C, 57.48; N, 5.56; N, 5.59; F, 3.79; P, 6.18
IR（KBr）（1587cm -1，C＝O COO -）
H 1-NMR composes (400MHz, CD 3OD):
δ 1.33（d，6H，J＝7Hz）
1.46-1.61（m，4H）
2.30（m，2H）
2.76（m，2H）
3.13(septet 1H, J7Hz)
4.14（m，1H）
7.17-7.30（m，9H）.
Embodiment 54
(S)-4-(((2-(cyclohexyl methyl)-4,6-3,5-dimethylphenyl) ethynyl) hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
A.N-(2,4-dimethyl benzene methylene radical) aniline
With reference to the United States Patent (USP) 4,375 of Merck, 475 the 39th pages
Title compound is prepared as described in embodiment 1A part.
With reference to the United States Patent (USP) 4,375 of Merck, 475 the 39th pages
Title pd-title complex is prepared as described in embodiment 1B part.
C.2-((cyclohexyl methyl)-4,6-dimethylbenzaldehyde
Magnesium chips that will be in argon gas atmosphere (1.44 grams, 59.45 mmoles) is with 15 milliliters of anhydrous Et 2O covers also sonication 5 minutes.Add cyclohexyl methyl bromine (1.5 milliliters) and continue sonication (in several minutes, beginning to reflux) to this magnesium chips.Add 60 milliliters of anhydrous Et along with continuing sonication simultaneously by feed hopper 25 milliliters of Et of O and remaining cyclohexyl methyl bromine 2O solution (adds 9.12 milliliters, 65.3 mmole cyclohexyl methyl bromines altogether.After adding, continue sonication 15 minutes, should reaction reflux 40 minutes then.With this Grignard reagent cooling room temperature, be added in the solution of the pd-title complex (5.55 grams, 7.43 mmoles) of B part and triphenylphosphine (15.59 grams, 59.45 mmoles) stirring 30 minutes in argon gas atmosphere and under the room temperature of this solution then by sleeve pipe.When adding Grignard reagent, this reaction solution becomes green and forms precipitation.This reaction solution at room temperature stirred 2 hours, then added 37 milliliters of 6N HCl.This mixture was stirred 1 hour, filter to remove solid by the Celite pad in the sintered glass funnel then.This solid Et 2O washing, filtrate through rotary evaporation to remove volatiles.
The gained resistates is in Et 2Stir among the O and as above filter.This filtrate with saturated NaCl solution washing once, organic phase MgSO 4Dry; Obtain 14.5 gram brown oil.Carry out purifying by dodging the formula chromatography, use 4%Et 2O/ hexane wash-out obtains the transparent oily matter of 1.70 grams, productive rate 99%.
TLC:Rf=0.30(5%Et 2The O/ hexane, silica gel).
IR（CHCl 3）3030，3008，2926，2853，1679，1606，1448，1147cm -1
1H NMR（270MHz-CDCl 3）
δ 10.51（s，1）
6.90（s，1）
6.85（s，1）
2.80（d，2，J＝6.0Hz）
2.55（s，3）
2.30（s，3）
1.80-1.55（m，5）
1.55-1.30（m，1）
1.30-0.80（m，5）
Mass spectrum (CI) m/e231(M+H) +
D.1-(cyclohexyl methyl)-and 2-(2, the 2-dibromo vinyl)-3, the 5-dimethyl benzene
Under argon gas atmosphere, with the aldehyde (1.68 grams, 7.30 mmoles) of C part at 65 milliliters of CH 2Cl 2In be cooled to 0 ℃.In this solution, add triphenylphosphine (6.13 grams, 23.4 mmoles) and stir this solution and all dissolve until all solids.Under 0 ℃, add CBr 420 milliliters of CH of (3.63 grams, 11.0 mmoles) 2Cl 2Solution.This reaction solution becomes orange.This reaction solution stirred 1.5 hours down at 0 ℃, used saturated NaHCO then 3Solution stopped reaction and vigorous stirring.Remove water layer and use CH 2Cl 2Extracting twice.Merge organic solution, use saturated NaHCO 3Washing is once used MgSO then 4Dry.Filtration also removes solvent, obtains 9.6 gram brown solid.By dodging the formula chromatography purification,, obtain 2.52 grams, the clear thorough oily matter of 90% productive rate with 100% hexane wash-out.
TLC:0.62(5%Et 2The O/ hexane, silica gel) PMA.
IR（CHCl 3）2925，2852，1608，1472，869cm -1
1HNMR（270MHz，CDCl 3）
δ 7.39（s，1）
6.87（s，1）
6.80（s，1）
2.37（d，2，J＝6.3Hz）
2.27（s 3）
2.24（s，3）
1.70（m，5）
1.45（m，1）
1.38-1.10（m，3）
0.90（m，2）
Mass spectrum: (CI) m/e 387(M+H) +
E.1-(cyclohexyl methyl)-and 2-ethynyl-3, the 5-dimethyl benzene
With the sym-dibromoethane based compound (2.51 grams, 6.5 mmoles) of D part in argon gas atmosphere with the THF(30 milliliter) stir and be cooled to-78 ℃.With adding n-Butyl Lithium (5.20 milliliters 2.5M hexane solutions) in 3 minutes times this dibromo compound solution under-78 ℃.The pink reaction solution of gained stirs under-78 ℃.After 1.5 hours, use saturated NH-78 ℃ of reactions 4The Cl aqueous solution stops this reaction, rises to room temperature then.Divide water-yielding stratum and use Et 2The O extracting twice, then once with hexane extraction.Merge all organic layers and use MgSO 4Drying is filtered and is removed and obtains 1.65 gram brown oil behind the solvent.Carry out purifying by sudden strain of a muscle formula chromatography, obtain the title acetylide of 1.39 grams, productive rate 95% with the hexane wash-out.
The TLC:0.50(5% toluene/hexane, silica gel), PMA.
IR（CHCl 3）3305，3007，2924，2852，2096，1607，1470，1448cm -1.
1H NMR（270MHz，CDCl 3）
δ 6.86（s，1）
6.79（s，1）
3.39（s，1）
2.63（d，2，J＝6.9Hz）
2.63（m，6）
1.20（m，3）
1.00（m，2）
Mass spectrum (CI) m/e227(M+H) +
F.(S)-4-(((2-(cyclohexyl methyl)-4,6-3,5-dimethylphenyl) ethynyl) methoxyl group phosphinyl)-3-(((1, the 1-dimethyl ethyl) diphenylmethyl silylation) oxygen) butyric acid, methyl esters
In argon gas atmosphere, E acetylide (1.36 grams, 6.0 mmoles) partly is cooled to-78 ℃ in 30 milliliters of anhydrous THF.Add n-Butyl Lithium (2.4 milliliters 2.5M hexane solutions) in this solution, this reaction solution becomes the burgundy look, stirs 1 hour down at-78 ℃.The phosphonyl chloride (4.68 grams, 9.6 mmoles) of embodiment 1F part is stirred and is chilled to-78 ℃ with 30 milliliters of anhydrous THF.With 15 minutes this alkynes negatively charged ion is imported in this phosphonyl chloride solution with sleeve pipe then.Finish after the transfer, this reaction solution stirred 1 hour down at-78 ℃, used saturated NH then 4Cl aqueous solution stopped reaction also rises to room temperature.From reaction mixture, remove THF, gained material Et 2O and H 2The O dissolving.Water layer Et 2O extraction 3 times.Merge all Et 2The O extraction liquid is also used saturated NaHCO 3Solution washing 1 time with salt water washing 1 time, is used MgSO then 4Dry.Filtration also removes solvent, obtains orange, carries out purifying by dodging the formula chromatography, with 3.5: 5.5: 1/EtOAC: hexane: the toluene wash-out.Obtain the acetylene phosphinate (2.80 grams, productive rate 70%) of title, be clear thorough oily matter.TLC: R f=0.37(5: 1: 4/ hexane: toluene: EtOAC, silica gel) PMA.
IR（CHCl 3）3025，3001，2929，2856，2164，1736，1607，1240，1112，1039，823cm -1.
1H NMR（270MHz，CDCl 3）
δ 7.66（m，4）
7.30（m，6），
6.87（s，1），
6.81（s，1）
4.66（m，1）
3.70&3.66（d′s，3，J＝14.3Hz）
3.56（s，3）
2.95（m，1）
2.69（m，1）
2.50（m，3）
2.32（m，2）
2.30（s，3）
2.27（s，3）
1.60（m，6）
1.03（m，3）
1.02（s，9）
0.95（m，2）
Mass spectrum (CI) m/e659(M+H) +
G.(S)-4-(((2-(cyclohexyl methyl)-4,6-3,5-dimethylphenyl) ethynyl) methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl esters
At room temperature, the acetylene phosphinate (0.633 gram, 0.96 mmole) with the F part stirs with 14.0 milliliters of anhydrous THF in argon gas atmosphere.Glacial acetic acid (0.22 milliliter, 3.84 mmoles) is added this phosphinate solution, then drip n-Bu with 5 fens clock times 4The 1.1M THF solution of NF(2.62 milliliter).After at room temperature stirring 19 hours, with frozen water this reaction is stopped, water layer extracts 3 times with EtOAC.The saturated NaHCO of organic solution that merges 3Solution washing 2 times, with saturated NaCl solution washing once.Organic layer Na 2SO 4Drying is filtered, and obtains yellow jelly (0.658 gram) after removing solvent.Carry out purifying by dodging the formula chromatography, use the EtOAC wash-out, obtain the alcohol (0.23 gram, 65%) of title, be clear thorough oily matter.
TLC:R f=0.51(6: 4 acetone/hexane, silica gel) PMA.
IR（CHCl 3）3450（br），3005，2926，2852，2164，1733，1607，1448，1439，1039cm -1.
1H NMR（270MHz，CDCl 3）.
δ 6.89（s，1）
6.82（s，1）
4.63（m，1）
3.88&3.87（2d′s，3，J＝12Hz）
3.69（s，3）
2.70（s，2）
2.62（d，2，J＝6.3Hz）
2.43（s，3）
2.32（s，3）
2.27（m，2）
1.65（m，6）
1.19（m，3）
1.00（m，2）
Mass spectrum (CI) m/e421(M+H) +
H.(S)-4-(((2-cyclohexyl methyl)-4,6-3,5-dimethylphenyl) ethynyl) hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
At room temperature, with G diester (0.212 gram stirs in the 0.51 mmole) Zai diox (7 milliliters), and adds 1.5 milliliters of 1N LiOH(1.5 mmoles) partly.This reaction is heated to 55 ℃, after 20 minutes, makes the precipitation solubilization of gained by adding 5 milliliters of dioxs and 4 ml waters.At 55 ℃ after following 2 hours 30 minutes, this reactant is chilled to room temperature, removes solvent under the decompression, and the gained white solid was placed 15 minutes under vacuum.This product carries out purifying on 3.0 * 19 centimetres of HP-20 resin columns, at first use 100 ml water wash-outs, then with 1: 1MeOH/H 2The O wash-out.The lyophilize product obtains 0.145 gram (71%) white lyophilize thing.
Rf=0.39(7: 2: 1 n-propyl alcohol/NH 4OH/H 2O, silica gel) PMA.
IR（KBr）3700-3100（br），2922，2850，2167，1590，1447，1179，1076cm -1.
1H NMR（400MHz，D 2O）
δ 6.99（s，1）
6.94（s，1），
4.53（m，1），
2.64（m，1），
6.22（d，2，J＝6.2Hz）
2.39（s，3）
2.37（m，1）
2.26（s，3）
2.02（m，2）
1.60（m，6）
1.14（m，3）
1.00（m，2）
Mass spectrum (FAB) m/e409(M+H) +, 397(M-2 Li+H) +
Ultimate analysis calculated value: C 21H 27O 5P Li 21.72H 2O:C, 57.96; H, 7.05; P, 7.12
Measured value: C, 57.96; H, 7.18; P, 6.96
Embodiment 55
4-((2-(2-(cyclohexyl methyl)-4,6-3,5-dimethylphenyl) vinyl) hydroxyl oxygen phosphino-)-and the 3-hydroxybutyric acid, dilithium salt
A.(E)-(2-(2-(cyclohexyl methyl)-4,6-3,5-dimethylphenyl) phosphonic acids vinyl), dimethyl ester
In argon gas atmosphere, will be in anhydrous THF(20 milliliter) in dimethyl methyl phosphonate (1.64 grams, 13.2 mmoles) be chilled to-78 ℃.With adding n-Butyl Lithium (5.0 milliliters 2.5M hexane solution, 12.4 mmoles) in this solution under 5 fens clockwise-78 ℃.After adding, milky reaction mixture was stirred 1 hour.In this anion solutions under-78 ℃, with 10 milliliters of the THF solution of the aldehyde (1.9 grams, 8.26 mmoles) that added embodiment 54A part in 10 minutes by feed hopper.After stirring 35 minutes under-78 ℃, use saturated NH 4The Cl aqueous solution (8 milliliters) stops this reaction, then it is heated to room temperature.Separate organic layer, water layer extracts 3 times with EtOAC.Merge organic phase and use the salt water washing once, use Na 2SO 4Dry.Filtration also removes solvent, obtains 3.25 gram yellow oil.
Top yellow oil (3.25 gram) is dissolved in the dry toluene, and by containing 4
Figure 881036994_IMG204
The soxhlet's extractor of molecular sieve refluxes.In the time of 0,3.5 and 18 hour, add tosic acid H 2The O(0.080 gram, 0.42 mmole).Reflux after 22 hours, this reaction is chilled to room temperature, vacuum removal toluene.The saturated NaHCO of yellow residuum in EtOAC of gained 3Solution washing twice is used Na 2SO 4Dry and filter, obtain yellow oil (A) after removing solvent.
This aqueous solution with EtOAC extraction 3 times, is used MgSO with dense HCl acidifying 4Solvent is filtered and removed to drying, obtains 0.535 gram yellow oil.Then with this yellow oil at 6.0 milliliters of HC(OCH 3) 3The middle backflow 24 hours then removes excessive HC(OCH under vacuum 3) 3This material and yellow oil (A) merge, and carry out purifying by dodging the formula chromatography, with 80%EtOAC/ hexane wash-out.Obtain the vinylphosphonate (2.07 grams, 73%) of title, be white solid.
TLC R f=0.45(1: 1 acetone/hexane, silica gel) PMA.
IR（KBr）2921，2851，1623，1447，1243，1186，1060，1027cm -1.
1H NMR（270MHz，CDCl 3）
δ 7.65（dd，1，J＝23.6Hz，18.1Hz）
6.88（s，1）
6.82（s，1）
5.80（dd，1，J＝21.0Hz，18.1Hz）
3.79（d，6，J＝11.5Hz）
2.49（d，2，J＝7.2Hz）
2.29（s，3）
2.28（s，3）
1.65（m，5）
1.45（m，1）
1.25-0.80（m，5）
Mass spectrum (CI) m/e337(M+H) +
B.(E)-(2-(2-(cyclohexyl methyl)-4,6-3,5-dimethylphenyl) phosphonic acids vinyl), methyl esters
At room temperature, the vinylphosphonate (2.07 grams, 6.16 mmoles) with the A part stirs with 14 milliliters of dioxs.In this solution, add 1.0N LiOH(9.24 milliliter, 9.24 mmoles), with this mixture heating up to 75 ℃.At 75 ℃ after following 3.5 hours, this reaction is chilled to room temperature, the vacuum removal diox.Gained residuum and H 2O stirs together and is acidified to pH～2 with 1N HCl.The aqueous solution is used Na with EtOAC extraction 3 times 2SO 4Solvent is filtered and removed to drying, obtains 1.95 gram pale solids.
TLC R f=0.58(8: 1: 1/CH 2Cl 2: CH 3OH: AcOH, silica gel), PMA.
1H NMR（270MHz，CDCl 3）
δ 12.11（s，1）
7.61（dd，1，J＝24.17Hz，17.58Hz）
6.87（s，1）
6.81（s，1）
5.88（dd，1，J＝21.43Hz，17.58Hz）
3.78（d，3，J＝11.54Hz）
2.47（d，2，J＝6.6Hz）
2.29（s，3）
2.28（s，3）
1.65（m，5）
1.45（m，1）
1.15（m，3）
0.95（m，2）
C.(E)-4-((2-(2-(cyclohexyl methyl)-4,6-3,5-dimethylphenyl) vinyl) methoxyl group phosphinyl)-the 3-ketobutyric acid, methyl esters
At room temperature in argon gas atmosphere, will be dissolved in 50 milliliters of anhydrous CH 2Cl 2The phosphonic acids mono-methyl (1.95 grams, 6.06 mmoles) and (C of B part 2H 5) 2NSi(CH 3) 3(1.76 grams, 12.1 mmoles) stirred 1 hour 25 minutes together.Vacuum removal CH 2Cl 2, gained yellow oil and benzene azeotropic were once placed 20 minutes very down at height then.In argon gas atmosphere, this oily matter is dissolved in anhydrous CH then 2Cl 2(50 milliliters) also are chilled to 0 ℃.Add two dry DMF, then slowly drip oxalyl chloride (0.92 gram, 7.27 mmoles), observed gas and emitted.This is reflected at 0 ℃ and stirred 15 minutes down, heats to room temperature then and stirs 1 hour.Vacuum removal CH from this reaction mixture 2Cl 2, gained orange and dry-out benzene azeotropic twice were taken out under high vacuum 1 hour then, obtained this phosphonyl chloride like this.
Be prepared as follows two negatively charged ion of methyl acetoacetate.In argon gas atmosphere, the NaH(0.25 gram oil suspension that will wash with pentane, 8.7 mmoles) in anhydrous THF(10 milliliter) in be chilled to 0 ℃.Methyl acetoacetate (0.92 gram, 7.9 mmoles) is added in the NaH suspension as 10 milliliters of THF solution, and stirred 20 minutes, add n-Butyl Lithium (2.90 milliliters of 2.5M hexane solutions, 7.3 mmoles) then, then stirred 45 minutes.This two anion solutions is chilled to-78 ℃, and 10 milliliters of THF solution of the phosphonyl chloride for preparing above are chilled to-78 ℃, with 15 minutes it is added in this two anion solutions then.After stirring 30 minutes under-78 ℃, use saturated NH 4The Cl aqueous solution stops this reaction, and heats to room temperature.From this reaction mixture, remove THF, and the gained orange is dissolved in 1: 1EtoAc/H 2Among the O.Water layer extracts 3 times with EtOAc.Merge the EtOAc extraction liquid and close NaHCO with satisfying 3Solution washing 2 times with saturated NaCl solution washing once, is used Na then 2SO 4Dry.By dodging this crude product of formula chromatography purification (2.75 gram), use the EtOAc wash-out, obtain the ketone ester (0.97 gram, 42%) of title, be yellow oil.
TLC R f=0.24(EtOAc, silica gel) PMA.
1H NMR（270MHz，CDCl 3）
δ 7.71（dd，1，J＝22.52Hz，18.13Hz）
6.89（s，1）
6.83（s，1）
5.89（dd，1，J＝26.37Hz，17.58Hz）
3.79（s，2）
3.73（s（br），6）
3.36（dd，2，J＝18.68Hz，5.5Hz）
2.50（m，2）
2.30（s，3）
2.29（s，3）
1.70（m，5）
1.45（m，1）
1.10-0.80（m，5）
D.4-((2-(2-(cyclohexyl methyl)-4,6-3,5-dimethylphenyl) vinyl) methoxyl group phosphinyl)-and the 3-hydroxybutyric acid, methyl esters
In argon gas atmosphere, with the β-oxo phosphonic acid ester (0.97 gram, 2.31 mmoles) of C part in the THF(10 milliliter) in stirring and be chilled to 0 ℃.With solid NaBH 4(0.087 gram, 2.31 mmoles) add in this THF solution, then drip 2 milliliters of CH 3OH, result have gas to emit.After stirring 50 minutes under 0 ℃,, then add CC-4 silica gel with 2 milliliters of acetone stopped reaction.This reaction solution heated filter to room temperature and by sintered glass.Remove solvent from filtrate, obtain yellow oil, it uses the EtOAC wash-out by sudden strain of a muscle formula chromatography purification.Obtain title alcohol, be clear thorough oily matter (0.65 gram, 66%).
TLC R f=0.29(50% acetone/hexane, silica gel) PMA.
M.P.80-83℃.
IR（KBr）3282（br），2923，2918，2848，1743，1614，1450，1442，1080，1045cm -1.
1H NMR（270MHz，CDCl 3）
δ 7.68（m，1）
6.88（s，1）
6.82（s，1）
5.89（m，1）
4.50（m，1）
4.00（m，1）
3.77&3.74（2 d′s，3，J＝11.0Hz）
3.69&3.68（2 s′s，3）
2.65（d，2，J＝6.0Hz）
2.50（m，2）
2.30（s（br），3）
2.28（s，3）
2.15（m，2）
1.68（m，5）
1.45（m，1）
1.30 to 0.80（m，5）
Mass spectrum (CI) m/e 423(M+H) +
E.4-((2-(2-(cyclohexyl methyl)-4,6-3,5-dimethylphenyl) vinyl) hydroxyl oxygen phosphino-)-and the 3-hydroxybutyric acid, dilithium salt
The diester (0.565 gram, 1.33 mmoles) of D part stirred until all solids with 14 milliliters of dioxs all enter solution.Add 1.0N LiOH(4.0 milliliter) and this solution is heated to 55 ℃.After 30 minutes, this reaction solution becomes muddiness.At 55 ℃ after following 2 hours, this reaction solution is chilled to room temperature, removes solvent on rotatory evaporator, obtains white solid.This crude product is purifying on the post of 3.0 * 15 centimetres of HP-20 resins, at first uses 100 milliliters of H 2The O wash-out is then used 75%MeOH/H 2The O wash-out.Lyophilize product fraction obtains title compound, is white freeze-drying body (0.524 gram, 98%).
TLC R f=0.41(7: 2: 1 n-propyl alcohol/NH 4OH/H 2O, silica gel) PMA.
IR（KBr）3700-3100（br），2921，2851，1591，1446，1222，1195，1161，1051cm -1.
1H NMR（400MHz，D 2O）
δ 7.25（dd，1，J＝18.68Hz）
6.98（s，1）
6.94（s，1）
6.00（dd，1，J＝17.95Hz）
4.33（m，1）
2.53（dd，1，J＝15.0Hz，4.4Hz）
2.49（d，2，J＝7.0Hz）
2.36（dd，1，J＝15.0Hz，8.43Hz）
2.27（s，3）
2.25（s，3）
1.89（dd，2，J＝14.3Hz，6.6Hz）
1.60（m，5）
1.45（m，1）
1.13（m，3）
0.95（m，2）
Mass spectrum (FAB) m/e407(M+H) +, 347(M +-2Li ++ 2H).
Analytical calculation value: C 21H 29O 5PLi 20.38H 2O:C, 61.03; H, 7.45; P, 7.49
Measured value: C, 61.03; H, 7.63; P, 7.66
Embodiment 56
(S)-4-((2-(2-(cyclohexyl methyl)-4,6-3,5-dimethylphenyl) ethyl) hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
A.4-(((2-(cyclohexyl methyl)-4,6-3,5-dimethylphenyl) ethyl) methoxyl group phosphinyl)-and 3-(((1, the 1-dimethyl ethyl) diphenylmethyl silylation) oxygen) butyric acid, methyl esters
With the methanol solution bubbling of argon gas by the acetylene phosphinate (1.33 grams, 2.02 mmoles) of 45 milliliters of embodiment 54F part 10 minutes.In this methanol solution in Parr bottle, add the 10%pd/C(0.34 gram).Hydrogenation 20 hours on the Pa Er device under 40psi after filtering by the Celite pad in the sintered glass funnel, obtains 1.39 gram oily matter.Carry out purifying by dodging the formula chromatography, with 1: 1EtOAC/ hexane wash-out, obtain title phosphinate (1.25 grams, 94%), be clear thorough oily matter.
TLC R f=0.21(5/4/1 hexane/EtOAC/ toluene, silica gel) PMA.
IR（CHCl 3）3600-3200（br），3003，2925，2853，1731，1448，1440，1247，1233，1179，1044cm -1.
1H NMR（270MHz，CDCl 3）
δ 6.83（s，1）
6.78（s，1）
4.50（m，1）
3.80&3.77（2 d′s，3，J＝6.3Hz）
3.72&3.71（2 s′s，3）
3.38（m，1）
2.87（m，1）
2.60（m，2）
2.45（d，2，J＝6.9Hz）
2.29&2.28（2 s′s，3）
2.25（s，3）
2.00（m，4）
1.70（m，6）
1.45（m，1）
1.30-0.90（m，6）
Mass spectrum (EI) m/e424(M) +
B.(S)-4-((2-(2-(cyclohexyl methyl)-4,6-3,5-dimethylphenyl) ethyl) methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl esters
At room temperature in argon gas atmosphere, with the silyl ether (1.2 grams, 1.8 mmoles) of A part in the THF(20 milliliter) in solution stir.In this solution, add 0.41 milliliter of Glacial acetic acid and n-Bu continuously 4The THF solution of NF(5.0 milliliter 1.1M, 5.44 mmoles), be dropwise to add with 5 minutes.After at room temperature stirring 23 hours, reaction is stopped and violent stirring with 50 milliliters of frozen water.Vacuum removal THF, gained material dilute with water and with EtOAc extraction 3 times.The saturated NaHCO of EtOAC extraction liquid 3Solution washing 2 times is also used the salt water washing once, uses Na then 2SO 4Dry.Filtration also removes solvent, obtains thorough clearly oily matter (1.3 gram).This product is used the 100%EtOAC wash-out by sudden strain of a muscle formula chromatography purification, obtains title alcohol (0.55 gram, 72%), is clear thorough oily matter.
R f=0.22(EtOAC, silica gel) PMA
IR（CHCl 3）2999，2950，2929，2856，1734，1244，1195，1183，1112，1105，1065，1043cm -1.
1H NMR（270MHz，CDCl 3）
δ 7.65（m，4）
7.28（m，6）
6.81（s，1）
6.76（s，1）
4.51（m，1）
3.62&3.60（2 d′s，3，J＝5.3Hz）
3.49&3.46（2 s′s，3）
2.97（m，1）
2.65（m，2）
2.35&2.33（2 d′s，2，J＝6.9Hz）
2.25（2 s′s，3）
2.16（2 s′s，3）
1.84（m，1）
1.68（m，6）
1.55（m，1）
1.18（m，2）
1.15（m，3）
1.00&0.99（2 s′s，9）
0.91（m，2）
Mass spectrum (CI) m/e 663(M+H) +
C.(S)-4-((2-(2-(cyclohexyl methyl)-4,6-3,5-dimethylphenyl) ethyl) hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
At room temperature, the diester (0.552 gram, 1.3 mmoles) with the B part stirs in 14 milliliters of dioxs.In this solution, add 1.0N LiOH(3.9 milliliter, 3.9 mmoles), then this reaction solution is heated to 55 ℃.Stir after 30 minutes, have the pie precipitation to form, by adding 5 milliliters of H 2O dissolves it.At 55 ℃ after following 2 hours 15 minutes, this reaction solution is chilled to room temperature, and the vacuum removal volatile matter obtains white solid.This product is purifying on 3.0 * 30 centimetres of HP-20 posts, earlier with 100 milliliters of H 2The O wash-out is then with 1: 1CH 3OH/H 2The O wash-out.Lyophilize product fraction obtains the white lyophilized products of 0.482 gram, productive rate 92%.
TLC R f=0.36(7: 2: 1 n-propyl alcohol/NH 4OH/H 2O, silica gel) PMA.
IR（KBr）3700-3100（br），2923，2852，1588，1446，1410，1159，1132，1048cm -1.
1H NMR（400MHz，D 2O）
δ 6.93（s，1）
6.91（s，1）
4.34（m，1）
2.80（m，2）
2.50（dd，1，J＝14.7Hz，4.4Hz）
2.48（d，2，J＝5.12Hz）
2.38（dd，1，J＝15.0Hz，6.6Hz）
2.29（s，3）
2.26（s，3）
1.84（m，2）
1.65（m，7）
1.48（m，1）
1.15（m，3）
1.00（m，2）
Mass spectrum (FAB) m/e 397(M+H-2L +) +, 409(M+H) +
Ultimate analysis calculated value: C 21H 31O 5PLi 20.76H 2O:C, 59.76; H, 7.77; P, 7.34
Measured value: C, 59.76; H, 7.91; P, 7.53
Embodiment 57
4-((((4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)-the 2-yl) oxygen) methyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
A.4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)-2-formaldehyde
With reference to the United States Patent (USP) 4,375 of Merck, 475 the 37th and 38 pages.
This title compound of preparation described in embodiment 1 part A～C.
B.4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)-2-methyl alcohol
In argon gas atmosphere, with the aldehyde of part A (1.03 grams, 4.26 mmoles) in 30 milliliters of anhydrous CH 2Cl 2In stir.At room temperature, with 15 minutes 20 milliliters of CH with metachloroperbenzoic acid (1.06 grams, 5.11 mmoles) 2Cl 2Solution splashes in this aldehyde solution.After at room temperature stirring 58 hours, this reaction mixture rotary evaporation is dissolved in the gained yellow solid then among the THF and with 6.4 milliliters of 2N KOH and handles to doing.This mixture at room temperature stirred 5.5 hours.From reaction solution, remove THF then.Gained resistates H 2The O dilution, this aqueous solution Et 2MgSO is used in O extraction 3 times then 4Dry this Et 2The O extraction liquid.Filter and remove that the yellow oily crude product of gained carries out purifying by dodging the formula chromatography behind the solvent, use 5%Et 2O/ hexane wash-out.Obtain the phenol of title, be white solid (0.843 gram, 100%).
TLC R f=0.37(10%Et 2The O/ hexane, silica gel) PMA
M.P.83-86℃.
IR（KBr）3512，3500（br），2950，1504，1482，1238，1231，1215cm -1.
1H NMR（270MHz，CDCl 3）
δ 7.20（m，2）
7.07（t，1，J＝9.0Hz）
6.92（s，1）
6.82（s，1）
4.95（s，1）
2.31（s，3）
2.25（s，6）
Mass spectrum (CI) m/e 231(M+H) +
C. (((4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)-the 2-yl) oxygen) methyl) phosphonic acids, diethyl ester
In argon gas atmosphere, the NaH(0.30 gram that will wash with pentane, 80% oil dispersion, 10.3 mmoles) suspension in 15 milliliters of dry DMF cools off with ice bath.Add in this NaH suspension with the solution of 15 minutes phenol with 10 milliliters of B parts (2.36 grams, 10.3 mmoles) in DMF, observed gas and emitted.After adding, heat this reaction solution to room temperature and stirred 35 minutes.At room temperature, with dripped in 10 minutes tosyloxy methyl-phosphorous acid diethyl ester (3.31 grams, 10.26 mmoles, for its preparation referring to Holy, A., Rosenberg, I.,
Collection Czechoslovak Chem.Commun., Vol.47,1982) 11 milliliters of DMF solution.After at room temperature 22 hours, use saturated NH 4The Cl aqueous solution stops reaction, then vacuum removal DMF.The gained solid is dissolved in EtOAC and H 2Among the O, water layer washs 2 times with EtOAC.The saturated NaHCO of EtOAC extraction liquid that merges 3MgSO is used in the aqueous solution and salt water washing then 4Dry.Filtration also removes solvent, obtains 4.3 gram title ether compound crude products, and it carries out purifying by dodging the formula chromatography, with 70%EtOAC/ hexane wash-out.Obtain the ether (3.2 grams, 82%) of title, be clear thorough oily matter.
TLC 0.52(50% acetone/hexane, silica gel) PMA.
IR（Film）2983，2925，2910，1504，1474，1213，1032，971cm -1.
1H NMR（270MHz，CDCl 3）
δ 7.33（m，2）
7.01（t，1，J＝10.0Hz）
6.96（s，1）
6.91（s，1）
4.07（m，4）
3.69（d，2，J＝9.3Hz）
2.34（s，3）
2.31（d，3，J＝1.7Hz）
2.29（s，3）
1.31（t，6，J＝7.0Hz）
Mass spectrum (CI) m/e 381(M+H) +, 242(M +-C 4H 10PO 3) +
D. (((4 '-fluoro-3,3,5 '-trimethylammonium (1,1 '-biphenyl)-the 2-yl) oxygen) methyl) phosphonic acids, mono ethyl ester
Under 70 ℃, with the diester (3.21 grams, 8.45 mmoles) of C part in 40 milliliters of dioxs with 12.7 milliliters of 1N LiOH(12.67 mmoles) stir.At 70 ℃ after following 3 hours, this reaction solution is chilled to room temperature, then the vacuum removal diox.Aqueous solution H 2The O dilution is also cooled off in ice bath, is acidified to pH～1 with 6N HCl then, obtains milky white solution.Then this solution is extracted 3 times with EtOAC; This EtOAC extraction liquid MgSO 4Dry also filtration obtains the transparent jelly of 3.12 grams.
TLC R f=0.20(9/0.5/0.5 CH 2Cl 2/ AcOH/MeOH, silica gel) PMA
1H NMR（270MHz，CDCl 3）
δ 10.26（s，1）
7.35（2）
6.96（m，3）
4.05（dq，2，J＝7.14Hz，14.8Hz）
3.63（d，2，J＝9.34Hz）
2.31（s，3）
2.29（s，3）
2.28（d，3，J＝2.2Hz）
1.28（t，3，J＝7.14Hz）
E.4-(oxyethyl group (((4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)-the 2-yl) oxygen) methyl) phosphinyl)-the 3-ketobutyric acid, methyl esters
In argon gas atmosphere, with the phosphonic acids (2.96 grams, 8.42 mmoles) of D part in 75 milliliters of anhydrous CH 2Cl 2In with (C 2H 5) 2Si(CH 3) 3(2.44 grams, 16.84 mmoles) at room temperature stir together.Stir after 1 hour 10 minutes vacuum removal CH 2Cl 2, gained oily matter and benzene azeotropic were once placed 15 minutes under high vacuum then.In argon gas atmosphere, this oily matter is dissolved in 75 milliliters of anhydrous CH 2Cl 2And be chilled to 0 ℃.Three dry DMF are added in this refrigerative solution, then drip oxalyl chloride (1.18 grams, 9.26 mmoles).This reaction solution stirred 20 minutes down at 0 ℃, heated to room temperature, and then stirred 1 hour.This reaction solvent of vacuum removal and oily phosphonyl chloride that should hestnut color and benzene azeotropic 2 times, placement 1 hour under high vacuum then.
Method described in two negatively charged ion of methyl acetoacetate such as embodiment 55 portion C is prepared (methyl acetoacetate (1.27 grams, 10.95 mmole), NaH(0.350 restrains oil dispersion, 12.05 mmole), n-Butyl Lithium (4.0 milliliters of 2.5M hexane solutions, 10.07 THF(35 milliliter mmole))).
The solution of the phosphonyl chloride for preparing above in 10 milliliters of THF that is chilled to-78 ℃ was added drop-wise to also in this two anion solutions of-78 ℃ with 20 minutes.After stirring 40 minutes under-78 ℃, use saturated NH down at-78 ℃ 4The Cl aqueous solution stops reaction, heats to room temperature.Vacuum removal THF, the gained resistates is dissolved in EtOAC and H 2Among the O.Water layer merges all EtOAC solution and uses saturated NaHCO with EtOAC extraction 2 times 3Solution washing once with the salt water washing once, is used Na then 2SO 4Dry.Obtain thick title phosphinate, for orange (4.0 gram), be purified, with 75%EtOAC/ hexane wash-out by dodging the formula chromatography.Obtain title phosphinate (1.4 grams, 42%) yellow oil.
TLC R f=0.25(75%EtOAC/ hexane, silica gel) PMA.
IR（CHCl 3）3004，2954，2925，1744，1718，1643，1541，1503，1472，1449，1438，1425，1236，1037cm -1.
1H NMR（270MHz，CDCl 3）
δ 7.30（m，2）
6.95（m，3）
4.05&3.90（2 m′s，2）
3.75（m，2）
3.73&3.66（2 s′s，3）
3.55（m，1）
3.25（m，1）
2.33&2.29（2 s′s（br），9）
1.28&1.12（2 t′s，3，J＝7.1Hz）
Mass spectrum (CI) m/e451(M+H) +
F.4-((((4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)-the 2-yl) oxygen) methyl) the oxyethyl group phosphinyl)-the 3-hydroxybutyric acid, methyl esters
In argon gas atmosphere, with the ketone (1.39 grams, 3.09 mmoles) of E part in the THF(15 milliliter) in solution be chilled to 0 ℃.In this refrigerative solution, add NaBH 4(0.12 gram, 3.09 mmoles) then slowly drip CH 3The OH(2.8 milliliter).At 0 ℃ after following 1 hour, with acetone, then add 1.4 gram CC-4 silica gel, reaction is stopped, heating to room temperature then.With this reacting liquid filtering, and, obtain yellow oil with the filtrate rotary evaporation.This oily matter dodges the formula chromatography, with 90%EtOAC/ hexane wash-out, merges the fraction that contains product, the vacuum removal solvent.The gained yellow oil is from Et 2Crystallization in the O/ hexane, gained crystal Et 2The O/ hexane is developed, and obtains the white crystal (0.320 gram) of title alcohol.
TLC R f=0.38(90%EtOAC/ hexane, silica gel) PMA.
M.P.116-119℃.
IR（KBr）3288（br），3000，2950，2920，1735，1503，1473，1440，1311，1232，1195cm -1.
1H NMR（270MHz，CDCl 3）
δ 7.28（m，2）
7.05（t，1，J＝6.0Hz）
6.98（s，1）
6.90（s，1）
4.42（m，1）
4.05&3.85（m，2）
3.75（d，2，J＝6.0Hz）
3.70（s，3）
2.55（m，2）
2.32（s，6）
2.30（s，3）
2.00（m，2）
1.30（t，3，J＝7.0Hz）
Mass spectrum (CI) m/e 453(M+H) +, 435(M-H 2O) +
G.4-((((4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)-the 2-yl) oxygen) methyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
At room temperature, with 1N LiOH(2.0 milliliter) add in 13 milliliters of dioxane solutions of F diester (0.293 gram, 0.65 mmole) partly.This reaction mixture is heated to 55 ℃ and stirred 1 hour 45 minutes, is chilled to room temperature then.This reaction mixture rotary evaporation obtains white solid to doing, and then it is placed 10 minutes under high vacuum.This crude product is chromatography purification on 3.0 centimetres of HP-20 posts of 15 cm x, and this post is earlier with 100 milliliters of H 2The O wash-out is then used 50%CH 3OH/H 2The O wash-out.Obtain pure title dilithium salt, be the lyophilized products (0.295 gram, 88%) of white.TLC R f=0.38(7: 2: 1 n-propyl alcohol/NH 4OH/H 2O, silica gel) PMA
IR（KBr）3400（br），3021，3011，2981，2958，2924，1575，1503，1475，1446，1430，1401，1231，1175，1087cm -1.
1H NMR（270MHz，D 2O）
δ 7.20（m，2）
7.07（d，1，J＝9.9Hz）
7.03（s，1）
6.86（s，1）
4.03（m，1）
3.40（d，2，J＝8.3Hz）
2.24（s，3）
2.21（s，3）
2.20（m，2）
2.17（s，3）
1.45（m，2）.
Mass spectrum (FAB) m/e423(M+H) +
Ultimate analysis calculated value: C 20H 22O 6FPLi 20.95H 2O:C, 54.67; H, 5.48; F, 4.32; P, 7.05
Measured value: C, 54.37; H, 5.03; F, 4.31; P, 7.55
Embodiment 58
4-(((4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)-the 2-yl) methyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
A.4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)-2-methyl alcohol
To NaBH 49 milliliters of EtOH(of (0.12 gram, 3.18 mmoles) are anhydrous) add the Et of the aldehyde (0.70 gram, 2.89 mmoles) of embodiment 57A part in the solution 2O-EtOH(4.5 milliliter/3.0 milliliter) solution.This reaction mixture at room temperature stirred 2 hours, used saturated NH then 4Cl solution stops reaction.By removing by filter the solid precipitation of gained.Filtrate rotary evaporation to dry doubling is dissolved in Et with the gained solid 2O and H 2Among the O.Water layer Et 2O washing 2 times, the Et of merging 2O solution MgSO 4Dry.
After filtering and removing solvent, obtain 0.70 gram white solid.This solid carries out purifying by dodging the formula chromatography, uses 33%Et 2O/ hexane wash-out, obtain 0.675 the gram (productive rate 100%) title alcohol.
TLC 0.11(15%Et 2The O/ hexane, silica gel) PMA.
M.P.101-102℃.
IR（KBr）3351，3293，3267，3260，3024，3016，2980，2939，2921，1605，1601，1502，1451，1355，1243，1236，1228，1189，1118，999cm -1.
1H NMR（270MHz，CDCl 3）
δ 7.15（m，2）
7.03（m，2）
6.90（s，1）
4.55（d，2，J＝6.0Hz）
2.48（s，3）
2.33（s，6）
Mass spectrum (CI) m/e 244(M +), 227(M +-OH)
B. ((4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)-the 2-yl) methyl) phosphonic acids, diethyl ester
In argon gas atmosphere, with 50 milliliters of CH of A alcohol (1.94 grams, 7.95 mmoles) partly 2Cl 2Solution is chilled to 0 ℃.In this refrigerative solution, add Et 3The N(0.965 gram, 9.54 mmoles), then drip methylsulfonyl chloride (MsCl) (1.00 grams, 8.75 mmoles).This reaction solution stirred 30 minutes down at 0 ℃, heated to room temperature then and stirred and spend the night.Use saturated NaHCO 3Solution stops and violent stirring reaction.The saturated NaHCO of organic layer 3Solution washing is used MgSO then 4Dry.Filtration also removes solvent, obtains 2.1 gram 2-(chloromethyls)-4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl), be transparent oily matter.
TLC R f=0.68(50%Et 2The O/ hexane, silica gel) PMA.
1H NMR（270MHz，CDCl 3）
δ 7.22（m，2）
7.03（m，2）
6.90（s，1）
4.50（s，2）
2.48（s，3）
2.33（s，6）
Need not be further purified, with top muriate (2.1 gram) under 150 ℃ in argon gas atmosphere with P(OC 2H 5) 3(30 milliliters) stirred 3 hours together.This reaction solution is chilled to room temperature, removes excessive P(OC by distillation 2H 5) 3This crude product carries out purifying by dodging the formula chromatography, with 70%EtOAc/ hexane wash-out.Obtain the phosphonic acid ester (2.40 grams, 83%) of title, be transparent oily matter.
TLC R f=0.37(70%EtOAC/ hexane, silica gel) PMA.
IR（CHCl 3）2992，2928，2909，1501，1474，1455，1443，1392，1245，1239，1119，1053，1029，970，963cm -1.
1H NMR（270MHz，CDCl 3）
δ 7.15（m，2）
7.00（m，2）
6.83（s，1）
3.83（m，4）
3.22（d，2，J＝22.52Hz）
2.47（s，3）
2.29（s，6）
1.16（t，6，J＝7.14Hz）
Mass spectrum (CI) m/e 365(M+H) +
C. ((4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)-the 2-yl) methyl) phosphonic acids, mono ethyl ester
At room temperature, the diethyl phosphonate (2.40 grams, 6.59 mmoles) with the B part stirs in 30 milliliters of dioxs.In Gai dioxane solution, add 1N LiOH(9.9 milliliter) and this reaction solution is heated to backflow.When 18 hours and 44 hours, add other 1N LiOH(9.9 milliliter more respectively).Reflux after 55 hours, this reaction solution is chilled to room temperature and removes diox on rotatory evaporator.Obtained aqueous solution H 2The O dilution is also used Et 2O extracts 2 times to remove any remaining diester.Then water layer is acidified to pH～1 with the ice bath cooling and with 6N HCl.This milky solution extracts 3 times with EtOAC, this EtOAC extraction liquid MgSO 4Drying is filtered, and removes solvent, obtains the transparent oily matter of 1.89 grams, productive rate 85%.
TLC R f=0.26(9/0.5/0.5, CH 2Cl 2/ MeOH/AcOH, silica gel) PMA.
IR（CHCl 3）3029，3023，3005，2983，2925，1710，1605，1500，1234，1042，988cm -1.
1H NMR（270MHz，CDCl 3）
δ 11.07（s，1）
7.05（m，2）
6.95（m，2）
6.80（s，1）
3.71（dq，2，J＝7.15Hz，14.83Hz）
3.13（d，2，J＝23.0）
2.38（s，3）
2.27（s，6）
1.13（t，3，J＝7.2Hz）.
Mass spectrum (CI) m/e 337(M+H) +
D.4-(oxyethyl group ((4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)-the 2-yl) methyl) phosphinyl)-the 3-ketobutyric acid, methyl esters
In argon gas atmosphere, with 50 milliliters of CH of C half acid (1.85 grams, 5.50 mmoles) partly 2Cl 2Solution and (C 2H 5) 2NSi(CH 3) 3(1.60 grams, 11.0 mmoles) at room temperature stirred 1 hour 15 minutes together.From this reaction mixture, remove CH 2Cl 2, gained yellow oil and benzene azeotropic once and under high vacuum were placed 20 minutes.This oily matter is dissolved in 50 milliliters of anhydrous CH under argon gas atmosphere 2Cl 2In and be chilled to 0 ℃.Two dry DMF are added in this refrigerative solution, then drip oxalyl chloride (0.768 gram, 6.06 mmoles), observed gas and emitted.This reaction solution stirred 20 minutes down at 0 ℃, heated to room temperature, and then stirred 1 hour 40 minutes; This reaction solution becomes the burgundy look.From reaction solution, remove CH 2Cl 2, gained oily matter and dry-out benzene azeotropic 2 times were placed 1 hour under high vacuum then.
Be prepared (methyl acetoacetate (0.830 gram, 7.16 mmoles) described in two negatively charged ion of this methyl acetoacetate such as the embodiment 57E part; NaH(0.230 restrains oil dispersion, 7.88 mmoles); N-BuLi(2.64 milliliter 2.5M hexane solution, 6.59 mmoles); 20 milliliters of THF).
The solution of the phosphonyl chloride for preparing above in 10 milliliters of anhydrous THF that is chilled to-78 ℃ was added in two anion solutions that are chilled to-78 ℃ by sleeve pipe with 20 minutes.After stirring 40 minutes under-78 ℃, use saturated NH 4Cl solution makes reaction stop under-78 ℃, heats then to room temperature; This reaction mixture H 2The O dilution is so that dissolved solids removes THF on rotatory evaporator.The gained mixture extracts 3 times with EtOAC.The saturated NaHCO of this EtOAC extraction liquid 3Washing once with the salt water washing once, is used MgSO 4Dry and filter, obtain the thick orange of 2.6 grams after removing solvent.This crude product carries out purifying by dodging the formula chromatography, with 75%EtOAC/ hexane wash-out.Obtain the ketone (0.43 gram, 23%) of D part, be orange foams.
TLC Rf=0.32(50% acetone/hexane, silica gel) PMA.
IR（KBr）2952，2925，1739，1718，1654，1529，1503，1472，1234，1206，1166，1119，1035cm -1.
1H NMR（270MHz，CDCl 3）
δ 7.20-6.70(aromatic series H ' s, 5)
4.00-3.70（m，2）
3.70&3.55（2 s′s，3）
3.35（m，2）
3.35（d，2，J＝15Hz）
2.92（m，1）
2.45&2.35（2 s′s，3）
2.25（s，6）
1.15&0.95（2 t′s，3，J＝7.0Hz）
Mass spectrum (CI) m/e 435(M+H) +
E.4-(oxyethyl group ((4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)-the 2-yl) methyl) phosphinyl)-the 3-hydroxybutyric acid, methyl esters
In argon gas atmosphere, with solid NaBH 4(0.035 gram, 0.92 mmole) is added in 5 milliliters of THF solution of D ketone (0.40 gram, 0.92 mmole) partly.At room temperature, methyl alcohol (0.80 milliliter) is added in this THF solution.After at room temperature 1 hour, reaction is stopped, then adding 0.4 gram CC-4 silica gel with acetone.Filter this reaction mixture and remove solvent.This reaction product has still kept some ketone raw material; Therefore, top reaction product is passed through above-mentioned identical reductive condition again; Yet, adding NaBH 4Before, with CO 2(g) bubbling is by this solution.As preceding carrying out aftertreatment, obtain 0.250 gram yellow oil, be purified by dodging the formula chromatography, use the EtOAC wash-out.Obtain pure title alcohol, be transparent oily matter.Wash-out.Obtain pure title alcohol, be transparent oily matter.
TLC R f=0.26(50% acetone/hexane, silica gel) PMA.
1H NMR（270MHz，CDCl 3）
δ 7.10（m，2）
7.00（m，2）
6.85（s，1）
4.28&4.03（2 m′s，1）
4.10-3.70（m，2）
3.67（s，3）
3.33（m，2）
2.47（s，3）
2.40（m，2）
2.30（s，6）
1.63（m，2）
1.17（t，3，J＝6.6Hz）
F.4-(((4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)-the 2-yl) methyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
In argon gas atmosphere, with the diester (0.110 gram, 0.252 mmole) of E part in anhydrous CH 2Cl 2Solution in (5.5 milliliters) is chilled to 0 ℃, and handles with collidine (Collidine, 0.046 gram, 0.38 mmole), then drips trimethylsilyl iodide (TMSI) (0.182 gram, 0.88 mmole).This reaction solution stirred 2 hours down at 0 ℃, heated to room temperature then.After 24 hours, add other properly mixed collidine (0.023 gram) and TMSI(0.091 gram again).After at room temperature stirring 48 hours, remove CH 2Cl 2, and 6 milliliters of dioxs are added in this oily matter, then add 1.7 milliliters of 1N LiOH.This mixture refluxed 16 hours, was chilled to room temperature and removed diox, obtained orange jelly.This jelly is dissolved in H 2Filter to remove solid among the O and by sintered glass.With this filtrate lyophilize, obtain the canescence lyophilized products, in the HP-20 post of 15 centimetres of 1.5 cm x, be purified.This post is earlier with 150 milliliters of H 2The O wash-out is used 50%MeOH/H then 2The O wash-out.With the lyophilize of product fraction, obtain title compound, be white freeze-drying body (88 milligrams, 80%).
TLC R f=0.38(7: 2: 1 n-propyl alcohol/NH 4OH/H 2O, silica gel), PMA.
IR（KBr）3700-3100（br），2923，1591，1501，1234，1147cm -1.
1H NMR（270MHz，D 2O）
δ 7.20-7.00（m，4）
6.82（s，1）
3.76（m，1）
3.11（m，2）
2.35（s，3）
2.22（s，3）
2.21（s，3）
2.05（m，2）
1.16（dd，2，J＝12.32Hz，6.45Hz）
Mass spectrum (FAB) m/e 407(M+H) +.
Ultimate analysis calculated value: C 20H 22FO 5PLi 20.80H 2O:C, 57.11; H, 5.65; F, 4.52; P.7.36
Measured value: C, 57.11; H, 6.63; F, 4.44; P, 7.70
Embodiment 59
(S)-4-(((1-4-fluorophenyl)-3-methyl-2-naphthyl) ethynyl) hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
A.1-methoxyl group-2-naphthoic acid
Reference: J.organomet.chem., 20(1969) 251～252 pages.Under argon gas atmosphere, with the n-BuLi(208.60 mmole, 83.44 milliliters of 2.5M hexane solutions Aldrich) stir in 42 milliliters of anhydrous cyclohexanes.This solution is chilled to 0 ℃ and also drips and handle (10 minutes) with distillatory Tetramethyl Ethylene Diamine (TMEDA) (208.6 mmoles, 24.24 grams, 31.48 milliliters).The gained slurry stirred 30 minutes down at 0 ℃, use 1-methoxynaphthalene (208.60 mmoles then, 33 grams, 30.28 milliliters) (Aldrich chem.co., need not be further purified and use) solution in 84 milliliters of anhydrous cyclohexanes drips and handles (20 minutes).Gained shiny red homogeneous reaction mixture is heated to room temperature and was stirred 2 hours.This reaction mixture is chilled to 0 ℃ and use CO by overlap to join in effective 30 minutes in batches 2Anhydrous Et under (gas) saturated-78 ℃ 2The o(250 milliliter) (CO in the solution 2The particle distillation is by containing SiO 2Drying tube, under-78 ℃ in anhydrous Et 2Bubbling among the o).The gained white slurry was heated to 0 ℃ with 45 minutes, used 450 milliliters of 5%Hcl(aqueous solution then) handle.Separate Et 2O, water layer Et 2O extraction three times.Merge organic extract liquid also with 3 * 150 milliliters of saturated NaHco 3(aqueous solution) extraction.Filter water layer removing insolubles by sintered glass funnel, this filtrate be chilled to 0 ℃ and with the slow acidifying of dense Hcl until pH=1.Filter the throw out of gained, with 2 * 150 milliliters of methylbenzene azeotropics, 50 ℃ under high vacuum dry 5 hours, obtain 32.52 gram (0.161 mole, productive rate 77%) 1-methoxyl groups-2-naphthoic acid, be pale powder, m.p.118～121.5 ℃.
TLC: silica gel, Rf=0.35 94: 5: 1/CH 2Cl 2: MeoH: CH 3CO 2H
1H NmR:(270MHz, CDCl 3) meet
13CNMR:(67.8MHz, CDCl 2) meet
Mass spectrum: CI m/e 203 +(M+H) +
IR:kBr meets
B.H-(2-hydroxyl-1, the 1-dimethyl ethyl)-1-methoxyl group-2-naphthalene carboxylic acid amides
Under argon gas atmosphere, with 1-methoxyl group-2-naphthoic acid (155.22 mmoles, 31.4 gram) in 155 milliliters of anhydrous CH 2Cl 2In stir.This solution SOCl then 2(310.44 mmoles, 36.94 grams, 22.65 milliliters) are handled.This reaction mixture at room temperature stirred 45 minutes, then reflux 45 minutes in 55 ℃ of oil baths.This reaction mixture is chilled to room temperature and handles with the thionyl chloride of additional content (18.47 grams, 11.32 milliliters), and reheat refluxed 45 minutes.This reaction mixture is chilled to room temperature, removes excessive SOCl by rotary evaporation under 35 ℃ 2And CH 2Cl 2(being discharged in the argon gas atmosphere) is dissolved in 155 milliliters of anhydrous CH with the solid of gained mustard then under argon gas 2Cl 2In.This solution is transferred in the feed hopper by sleeve pipe and drip (40 minutes) to 155 milliliters of anhydrous CH of the 2-amino-2-methyl propyl alcohol that is stirring (310.44 mmoles, 27.67 grams) under 0 ℃ in argon gas 2Cl 2Solution in.The gained reaction mixture is heated to room temperature and was stirred 18 hours.Filter this reaction mixture then, throw out CH 2Cl 2Washing, vacuum-evaporation filtrate.Resistates is dissolved among 350 milliliters of EtOAC more also with 1 * 250 milliliter of H 2O, 1 * 250 milliliter of 5%HCl, 1 * 250 milliliter of 5%NaOH and the washing of 1 * 250 mL of saline.Each personal EtOAC of water extraction liquid strips once.Merge organic extract liquid, use MgSO 4Drying is filtered, and vacuum-evaporation obtains orange, and it was taken out under high vacuum 8 hours with 250 milliliters of methylbenzene azeotropics and at 55 ℃, obtains 38.2 and restrains (139.76 mmoles, productive rate 90%) title naphthalene diamide, is light yellow solid.
TLC: silica gel, Rf=0.65 100% EtOAC
1H NMR（270MHz，CDCl 3）
δ 8.19（s，br，1H）
8.14（m，1H）
8.03（d，1H，J＝8.7Hz）
7.83（m，1H）
7.66（d，1H，J＝8.7Hz）
7.55（m，2H）
4.00（s，3H）
3.74（s，2H）
1.47（s，6H）
Mass spectrum: CI m/e 274(M+H) +
IR:(CHCl 3Solution)
3365，3063，3024，3005，2971，2938，2873，1641，1597，1540，1456，1446，1387，1371，1344，1291，1256，1238，1223，1210，1199，1183，1168，1145，1079，981，833cm -1.
C.4,5-dihydro-2-(1-methoxyl group-2-naphthyl)-4,4-Er Jia Ji oxazole
The naphthalene diamide (139 mmoles, 38.2 grams) of B part is stirred and is chilled to 0 ℃ in argon gas, toward wherein dripping (15 minutes) thionyl chloride (0.556 mole, 66.15 grams, 40.56 milliliters).Gained dun oily matter at room temperature stirred 45 minutes.Add anhydrous Et 2The O(500 milliliter), and with this reaction mixture mechanical stirring 2.5 hours.Filter the yellow crystals precipitation of gained, use Et 2The O washing is suspended in 250 milliliters of Et then 2Among the O.This suspension is chilled to 0 ℃ also with～200 milliliters of 10%NaOH alkalization.Water layer Et 2O extraction 3 times, with the EtOAC extraction once.Merge organic extract liquid, with the salt water washing once, concentrate, use MgSO 4Dry also filtration.This filtrate and toluene vacuum azeotropic were taken out resistates 8 hours at 55 ℃ then under high vacuum, (0.126 mole, productive rate 90%) Biao Ti oxazoline is golden yellow powder to obtain 32.10 grams.
TLC: silica gel Rf=0.37 50% EtOAC
1H NMR：（270MHz，CDCl 3）
δ 8.25（m，1H）
7.84（d，1H，J＝8.7Hz）
7.84（m，1H）
7.60（d，1H，J＝8.7Hz）
7.54（m，2H）
4.19（s，2H）
4.04（s，3H）
1.46（s，6H）
Mass spectrum: CI m/e 256(M+H) +
IR：2969，2935，2896，1642，1465，1447，1386，1372，1349，1255，1109，1074，991cm -1.
D.2-(1-(4-fluorophenyl)-2-naphthyl))-4,5-dihydro-4,4-Er Jia Ji oxazole
In argon gas, C Bu Fen De oxazoline (117.52 mmoles, 30.0 grams) is stirred in 352.5 milliliters of anhydrous THF.This solution is heated to 45 ℃ in oil bath.Remove thermal source, drip (30 minutes) 4-fluorophenyl magnesium bromide in Et～45 ℃ speed to be enough to keep temperature of charge 2O(Aldrich) the 2M solution in (158.65 mmoles, 79.33 milliliters.After adding, this reaction mixture remains on 45 ℃, simultaneously this reaction mixture is stirred 18 hours.This reaction mixture is chilled to 0 ℃ also with 200 milliliters of saturated NH 4The Cl(aqueous solution) stopped reaction is with 200 milliliters of H 2O and 200 milliliters of EtOAC dilute this reaction mixture.Water layer extracts 4 times with EtOAC.Merge organic extract liquid, concentrate, use MgSO 4Dry also filtration.Vacuum-evaporation filtrate obtains the dark golden solid of 39 grams.This product carries out purifying (post of 95 mm dias, 7 " Merck silica gel, 25%EtOAC/ hexane elutriant; 2 by dodging the formula chromatography " / minute flow velocity), obtain the naphthalene of the 4-fluorophenyl replacement of 30.42 gram (95.25 mmoles, productive rate 81%) titles, be light yellow solid, m.p.94～96 ℃.Get back 3.38 the gram (10.58 mmoles, 9%) impure a little products.
TLC: silica gel Rf=0.45 50% EtOAC/ hexane
1H NMR：（270MHz，CDCl 3）
δ 7.93-7.13（aromatic，10H）
3.77（s，2H）
1.27（s，6H）
Mass spectrum: CI m/e 320(M+H) +
IR：（KBr）3060，2966，2927，2884，1667，1603，1508，1462，1383，1354，1335，1293，1219，1185，1160，1119，1083，978，842，830cm -1.
E.2-(1-(4-fluorophenyl)-3-methyl-2-naphthyl))-4,5-dihydro-4,4-Er Jia Ji oxazole
In argon gas with the 1-4-fluorophenyl-2-oxazoline Haphthyl compounds (87.67 mmoles, 28 grams) of D part in 585 milliliters of anhydrous Et 2Stir among the O.This solution is chilled to-25 ℃ and also uses n-BuLi(140.27 mmole, the hexane solution of 56.1 milliliters of 2.5M) drip and handled 1 hour.In the reinforced process of this 1 little duration, this reaction mixture changes garnet/orange solution into by yellow homogeneous phase solution, change into again have sedimentary orange/green solution.This reaction mixture is used methyl iodide (263.01 mmoles, 37.33 grams, 16.4 milliliters) to drip (15 minutes) then and is handled-25 ℃ of following restir 2.5 hours.The dark burgundy solution of gained stirred 4.5 hours down at-25 ℃, heated to 0 ℃ and stirred 16 hours, heated to room temperature at last and stirred 7 hours.The gained yellow transparent solution is with 500 milliliters of ice-cold salt solution stopped reaction.Water layer extracts 4 times with EtOAC.Merge organic extract liquid, concentrate, use MgSO 4Dry and filter by florisil (Florisil, 300 milliliters of sintered glass funnels, whole 2/3).Use CH 2Cl 2Wash this florisil.Concentrated filtrate with methylbenzene azeotropic and vacuum-evaporation, was taken out under high vacuum 3 hours at 55 ℃ then, obtained the methylated naphthalene of 30.32 gram (" 90.94 mmole ", productive rate 100%) titles, was yellow solid.
TLC: silica gel R f=0.50 50% EtOAC/ hexane
1H NMR：（270MHz，CDCl 3）
δ 7.79-7.07(aromatic series, 9H)
3.80（s，2H）
2.54（s，3H）
1.13（s，6H）
Mass spectrum: CI m/e 334(M+H) +
IR:(CHCl 3Solution)
3013，2967，2931，2895，2870，1667，1605，1513，1497，1461，1299，1280，1235，1190，1158，1041，965，841cm -1.
F.2-(1-(4-fluorophenyl)-3-methyl-2-naphthyl))-4,5-dihydro-3,4,4-San Jia Ji oxazole iodide
In argon gas, E Bu Fen De oxazoline (87.67 mmoles, 29.23 grams) is stirred in 140.28 milliliters of Nitromethane 99Min.s.This solution is handled with a collection of adding of methyl iodide (0.789 mole, 112 grams, 49.2 milliliters).Do not having under the condition of light, gained browning reaction mixture was being heated 1 hour 20 minutes in 60 ℃ of oil baths.Remove methyl iodide by simple distillation.By rotary evaporation, then under high vacuum, took out 45 minutes, remove Nitromethane 99Min..Gained burgundy look solid is in 250 milliliters of anhydrous Et 2Mechanical stirring is 1 hour among the O.Incline this redness filtrate and solid used Et as mentioned above again 2The O development.Filter the yellow solid of gained, under high vacuum, take out 4 hours (not having under the condition of light), obtain Biao Ti oxazoline iodide 44 grams (" 92.63 " mmole, productive rate 100%).Be the mustard solid.This title compound was stored 18 hours in-30 ℃ of following lucifuges, was directly used in the compound of preparation G part then.
TLC: silica gel R f=0.30 10% MeOH/CH 2Cl 2
G.1-(4-fluorophenyl)-3-methyl-2-naphthaldehyde
In argon gas with F Bu Fen De oxazoline iodide (87.67 mmole) in 526 milliliters of anhydrous THF and 210 milliliters of anhydrous EtOH(with 4
Figure 881036994_IMG205
Molecular sieve drying is crossed) in stir.This solution/suspension is chilled to-15 ℃, and uses NaBH in batches 4Handle (in 1 hour).After adding, this reaction solution stirred 2.5 hours down at-10 ℃～-15 ℃.Then, dilute this solution with 210 milliliters of anhydrous EtOH, this reaction mixture stirs under-15 ℃, simultaneously with 45 minutes dropping 2N HCl(438 milliliters, 876 mmoles) very slow when beginning to drip).After adding, this reaction mixture is heated to room temperature and was stirred 4 hours.Use 500 milliliters of H then 2Et is then used in the O dilution 2The O aqueous layer extracted.Merge organic extract liquid, concentrate, use MgSO 4Drying is filtered, and concentrates, and with toluene (2 * 120 milliliters) azeotropic, vacuum-evaporation, obtains the aldehyde of 12.9 gram (48.81 mmoles, productive rate 56%) titles, is light yellow solid.
TLC: silica gel R f=0.66 50% EtOAC/ hexane
1H NMR：（270MHz，CDCl 3）
δ 10.0（s，1H）
20 7.83-7.18(aromatic series, 9H)
2.81（s，3H）
Mass spectrum: CI m/e 265(M+H) +
IR:(CHCl 3Solution)
1685，1512，1422，1237，862cm -1.
H.2-(2.2-dibromo vinyl)-the 1-(4-fluorophenyl)-the 3-methylnaphthalene
In argon gas with the aldehyde (11.35 mmoles, 3.0 grams) of G part in 113.5 milliliters of anhydrous CH 2Cl 2In stir.This solution is chilled to 0 ℃, uses a collection of adding of triphenylphosphine (36.32 mmoles, 9.53 grams) to handle then.This reaction mixture stirred 20 minutes down at 0 ℃, dripped carbon tetrabromide (18.16 mmoles, 6.02 grams) then in 41 milliliters of anhydrous CH 2Cl 2In solution handle (20 minutes).Stirred 1 1/4 hours down at 0 ℃, solution is by the dark orange dark burgundy that becomes.This reaction mixture is with 150 milliliters of saturated NaHCO then 3(aqueous solution) stopped reaction.With water layer CH 2Cl 2Extract 4 times, merge organic extract liquid, vacuum concentration with the salt water washing once, is used MgSO 4Dry also filtration.This filtrate preabsorption is arrived on the Merck silica gel (～28 gram), be added to then and contain 6 " on the sudden strain of a muscle formula chromatography column of 50 mm dias of Merck silica gel, with 7%EtOAC/ hexane elutriant wash-out, washing speed 2 "/minute, obtain 4.23 gram title dibromo alkene, be not too pure light yellow solid.Then use the hexane recrystallization, obtain 3.68 gram (8.77 mmoles, productive rate 77%) title dibromo alkene, be the white powder solid.m.p.＝134.5～135.5℃。
TLC: silica gel R f=0.60 20% EtOAC/ hexane
1H NMR：（270MHz，CDCl 3）
δ 7.79～7.11(aromatic olefin, 10H), 2.48(S, 3H)
Mass spectrum: CI m/e 419/421/423(M+H) +
IR:(CHCl 3Solution)
3016，1604，1512，1496，1234，1220，1208，1158，886，858cm -1
I.2-ethynyl-1-(4-fluorophenyl)-the 3-methylnaphthalene
Dibromo alkene (8.7 mmoles, 3.69 grams) with the H part in argon gas stirs in 47.9 milliliters of anhydrous THF.This solution is chilled to-78 ℃, drips the n-BuLi(17.4 mmole then, 6.96 milliliters of 2.5M hexane solutions-Aldrich) handle (15 minutes).This reaction mixture stirred 1 hour down at-78 ℃, used 40 milliliters of saturated NH then 4The Cl(aqueous solution) stopped reaction.Heat after 0 ℃, with 40 milliliters of H 2O and 40 milliliters of Et 2O dilutes this reaction mixture.Water layer Et 2O extraction 2 times, with the EtOAC extraction once.Merge organic extract liquid, use MgSO 4Drying is filtered and vacuum evaporating solvent.Carry out preliminary purification (50 millimeters column diameters, 6 " Merck silica gel, 7%EtOAC/ hexane elutriant, 2 "/minute flow velocity) by dodging the formula chromatography, obtain the green oily matter/solid of 2.32 grams.270MHz 1It is impure product for the HNMR proof.Carry out the repurity (post of 75 milliliters of diameters by dodging the formula chromatography, 6 " Merck silica gel; 1%EtOAC/ hexane elutriant; 2 " / minute flow velocity), obtain 2.11 gram (8.11 mmoles, productive rate 93%) title acetylide is light blue solid (taking out 8 hours) m.p.=91.5～94.5 ℃ under high vacuum.
TLC: silica gel, PMA R f=0.56 20%EtOAC/ hexane
1H NMR：（270MHz，CDCl 3）
δ 7.77-7.13(aromatic series, 9H)
3.18（s，1H）
2.62（s，3H）
Mass spectrum: CI m/e 260M +
IR:(CH 2Cl 2Film)
3291，1604，1512，1494，1383，1222，1158，1150，1092，884，871，853，825cm -1.
J.(S)-and 3-(((1, the 1-dimethyl ethyl) diphenylmethyl silylation) oxygen)-4-(((1-(4-fluorophenyl)-3-methyl-2-naphthyl) ethynyl) methoxyl group phosphinyl) methyl-butyrate
With the dicyclohexyl amine salt of embodiment 25 (8.82 mmoles, 5.57 grams) 1: 1EtOAC/5%KHSO 4Distribute between the mixture of (each 150 milliliters), and acutely shake.Separate each layer, the EtOAC layer is with 2 * 100 milliliters of fresh 5%KHSO 4Washing.At last, use MgSO 4Dry organic layer filters and the vacuum removal solvent.Gained resistates and 2 * 120 milliliters of benzene azeotropics, evaporation was also taken out under high vacuum 2 hours, obtained the phosphonate monoester of " 4.33 gram ", " productive rate 109% ", was the heavy-gravity light yellow oil.Under argon gas with this oily matter in 24.8 milliliters of anhydrous CH 2Cl 2The middle stirring handled (8 minutes) toward wherein dripping distillatory diethyl trimethyl silyl amine (17.64 mmoles, 2.56 grams, 3.34 milliliters).This solution at room temperature stirred 2 hours.Then, on rotatory evaporator, remove volatilization component (entering in the argon gas), gained resistates and 1 * 60 milliliter of dry-out benzene azeotropic, vacuum-evaporation was also taken out under high vacuum 45 minutes.Then in argon gas with this resistates in 24.8 milliliters of anhydrous CH 2Cl 2The middle stirring.Add two DMF and this solution is chilled to 0 ℃.Drip (10 minutes) oxalyl chloride (10.58 mmoles, 1.34 grams, 0.923 milliliter).The gained amber solution stirred 30 minutes down at 0 ℃.Heat to room temperature and stirred 2 hours.According to the method described above, remove volatile matter, resistates and dry benzene azeotropic are also handled under high vacuum.At last, in argon gas, resistates is stirred in 27.7 milliliters of anhydrous THF.This solution is chilled to-78 ℃, will drip (15 minutes) with anionic-78 ℃ THF solution of the acetylene that following method makes and handle in phosphonyl chloride.
In argon gas, the acetylide (5.19 mmoles, 1.35 grams) of I part is stirred in 27.7 milliliters of anhydrous THF and be chilled to-78 ℃.In this solution, drip the n-BuLi(5.19 mmole, 2.08 milliliters 2.5M hexane solution) processing (10 minutes).The gained green solution stirred 1.5 hours down at-78 ℃, heated to 0 ℃ of maintenance 15 minutes, and then was chilled to-78 ℃.This solution is remained on-78 ℃.Simultaneously it is transferred in the dropping funnel in batches and be added drop-wise in-78 ℃ the THF solution of top formed phosphonyl chloride.After adding, this reaction mixture stirred 1 hour down at-78 ℃, used 50 milliliters of saturated NH then 4The Cl(aqueous solution) stopped reaction, and heat to 0 ℃.Use 40 milliliters of H then 2O and 40 milliliters of Et 2O dilutes this reaction mixture.Water layer is with 4 * 50 milliliters of Et 2The O extraction.Merge organic extract liquid, concentrate, use MgSO 4Drying is filtered the vacuum removal solvent.(post of 75 mm dias, 6 " Merck silica gel, 5: 4: 1 hexanes: EtOAC: toluene elutriant, 2 "/minute flow velocity separates this product, obtains 1.53 gram (2.21 mmoles, productive rate 43%) title acetylene phosphinates, is yellow foams by sudden strain of a muscle formula chromatography.Also reclaimed the impure raw material of 0.589 gram.
TLC: silica gel, 5: 4: 1 hexanes of pMA Rf=0.26: EtOAC: toluene
1H NMR：（270MHz，CDCl 3）
δ 7.82-7.09(aromatic series, 19H)
4.52（m，1H）
3.60&3.59（2 x s，3H）
3.36&3.31（2 x d，3H，J＝11.5Hz）
2.54&2.49（2 x s，3H）
2.87-2.73（m，1H）
2.61-2.56（m，1H）
2.39-2.22（m，1H）
2.12-2.00（m，1H）
1.02（s，9H）
Mass spectrum: CI m/e 693(M+H) +
IR:(CHCl 3Solution)
3004，2951，2932，2858，2164，1735，1605，1512，1494，1472，1437，1427，1237，1197，1182，1158，1151，1138，1110，1105，1093，1038，1017，951，885，834cm -1.
K.(S)-4-(((1-(4-fluorophenyl)-3-methyl-2-naphthyl) ethynyl) methoxyl group phosphinyl)-the 3-beta-hydroxymethyl butyrate
Acetylene phosphinate (0.866 mmole, 0.60 gram) with J part in argon gas stirs in 10.5 milliliters of anhydrous THF, and with Glacial acetic acid (3.46 mmoles, 0.208 gram, 0.198 milliliter) handle, then drip tetrabutylammonium fluoride (2.60 mmoles, 2.36 milliliters of 1.1M THF solution).This reaction mixture at room temperature stirred 24 hours, used 25 milliliters of frozen water stopped reaction then, and diluted with EtOAC.Water layer extracts 3 times with EtOAC.Merge organic extract liquid, use saturated NaHCO 3(aqueous solution) washing once with the salt water washing once, is used MgSO 4Drying is filtered and vacuum-evaporation.This product carries out purifying by sudden strain of a muscle formula chromatography and (uses the post of 30 mm dias; 35: 1Merck silica gel, 100%EtOAC elutriant, 2 "/minute flow velocity), obtain 0.267 gram (0.588 mmole, productive rate 68%) title beta-hydroxy phosphinate, be light yellow foams.
TLC: silica gel, pMA Rf=0.28 100% EtOAC
1H NMR：（270MHz，CDCl 3）
δ 7.81-7.18(aromatic series, 9H)
4.38（m，1H）
3.71（s，3H）
3.59&3.58（2 x d，3H，J＝12Hz）
2.66&2.65（2 x s，3H）
2.62-2.52（m，2H）
2.19-1.92（m，2H）
Mass spectrum: CI m/e 455(M+H) +
The IR:(film)
3380（broad），3065，3048，2993，2951，2166，1738，1604，1513，1495，1457，1438，1423，1401，1385，1378，1334，1299，1222，1179，1160，1138，1095，1035，951，887，836cm -1
L.(S)-4-(((1-(4-fluorophenyl)-3-methyl-2-naphthyl) ethynyl) hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
Stir in 6 milliliters of dioxs of diester (0.583 mmole, 0.265 gram) with K part in argon gas and with 1N LiOH(1.75 mmole, 1.75 milliliters) processing.This reaction mixture heated 45 minutes in 70 ℃ of oil baths.This reaction mixture is chilled to room temperature.By rotary evaporation, then under high vacuum, take out and removed solvent in 1 hour.The gained white solid is dissolved in 4 ml distilled waters, and is added on the Hp-20 chromatography column (17.0 centimetres of 2.5 cm x, watering balance).This post is with 250 milliliters of H 2The O wash-out is then with 45: 55MeOH: H 2The O wash-out.Per 1.3 minutes (m) collects fraction (～10 milliliters).35 ℃ of following vacuum-evaporation product fractions, lyophilize, under high vacuum in P 2O 5On took out 8 hours, obtain 0.237 the gram (0.541 mmole, productive rate 93%) title phospho acid dilithium salt, be white lyophilized products.
TLC: silica gel, pMA Rf=0.40 7: 2: 1
n-C 3H 7OH/NH 4OH/H 2O
1H NMR：（400MHz，D 2O）
δ 7.88（d，1H，J＝8.43Hz）
7.80（s，1H）
7.58-7.29(aromatic series, 7H)
4.14-4.05（m，1H）
2.61（s，3H）
2.43（dd，1H，J＝3.67，J＝15.39）
2.21（dd，1H，J＝9.16，J＝15.39）
1.84-1.67（m，2H）
Mass spectrum: FAB m/e 439(M+2 Li) +
IR：（KBr）3443-3260（broad），3066，2164，1594，1512，1495，1434，1222，1183，1160，1071，834cm -1.
Ultimate analysis calculated value C 23H 18FO 5PLi 2+ 0.66 mole of H 2O
M.W.＝450.14：C，61.38;H，4.33;F，4.22;P，6.88
Measured value: C, 61.38; H, 4.07; F.4.42; P, 6.80
Embodiment 60
(E)-4-((2-(1-(4-fluorophenyl)-3-methyl-2-naphthyl) vinyl) hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
A. phosphonic acids (2-(1-(4-fluorophenyl)-3-methyl-2-naphthyl)-2-hydroxyethyl), dimethyl ester
In argon gas with dimethyl methyl phosphonate (24.21 mmoles, 3.0 the gram, 2.62 milliliters) in anhydrous THF(47 milliliter) in the stirring.This solution is chilled to-78 ℃, drips the n-BuLi(22.70 mmole then, 9.08 milliliters 2.5M hexane solution) processing (15 minutes).This reaction mixture stirred 1.5 hours down at-78 ℃, dripped the aldehyde (15.13 mmoles, 4.0 restrain) of embodiment 59G part in anhydrous THF(14 milliliter then in the gained milky solution) in solution-treated (15 minutes).This reaction mixture stirred 45 minutes down at-78 ℃.At last, the saturated NH of this reaction mixture 4The l aqueous solution (50 milliliters) stopped reaction is heated to room temperature, uses H 2The O(50 milliliter) and the EtOAC(50 milliliter) dilution.Water layer extracts 4 times with EtOAC.Merge organic extract liquid, use MgSO 4Drying is filtered, and concentrates, and uses methylbenzene azeotropic 2 times, and vacuum-evaporation is taken out under high vacuum, obtains 5.90 gram (15.13 mmoles, productive rate 100%) title phosphonic acid esters, is yellow solid, and it is directly used in the compound of preparation B part.
TLC: silica gel, pMA Rf=0.37 50% acetone/hexane
B.(E)-(2-(1-(4-fluorophenyl)-3-methyl-2-naphthyl) phosphonic acids vinyl), dimethyl ester
Beta-hydroxy phosphonic acid ester (14.16 mmoles, 5.5 grams) with the A part in argon gas stirs in 66.5 milliliters of dry toluenes.This solution tosic acid monohydrate (TSOHH 2O) (3.54 mmoles, 0.673 gram) handled.This reaction mixture is reflux in 135 ℃ of oil baths.Phlegma is contained exsiccant 4 by one
Figure 881036994_IMG206
The apparatus,Soxhlet's of molecular sieve.Reflux after 16 hours, add TSOH: H again 2The O(2.12 mmole, 0.404 gram), this reaction mixture is reheat 8.5 hours as above.This reaction mixture is chilled to room temperature, with 100 milliliters of EtOAC dilutions.This mixture is with 100 milliliters of saturated NaHCO then 3(aqueous solution) washing.Water layer extracts 4 times with EtOAC.Merge organic extract liquid, use MgSO 4Drying is filtered and vacuum-evaporation, obtains the thick vinylphosphonate of 4.22 grams, is brown solid.Water layer 5%HCl acidifying is then with EtOAC extraction 3 times.Merge organic extract liquid, use MgSO 4Drying is filtered and evaporation, obtains 1.4 gram (" 3.92 mmole ") vinyl phosphonic acid monoesters, is light brown solid.In argon gas, this solid is stirred in trimethyl orthoformate (15 milliliters), and in 120 ℃ of oil baths reflux 16 hours.This reaction mixture is chilled to room temperature.The trimethyl orthoformate that vacuum removal is excessive, this resistates and above-mentioned 4.22 gram crude ethylene base phosphonic acid esters merge.This product carries out purifying by sudden strain of a muscle formula chromatography (post of 75 milliliters of diameters, 6 " Merck silica gel, 100%EtOAC elutriant, 2 "/minute flow velocity), obtains 3.70 gram (9.99 mmoles, productive rate 71%) title vinylphosphonates, is the peachiness solid.
TLC: silica gel, pMA Rf=0.48 100%EtOAC
1H NMR：（270MHz，CDCl 3）
δ 7.79（d，1H，J＝8.4Hz）
7.72（s，1H）
7.56-7.13（m，8H）
5.54（dd，1H，J＝17.93Hz，J＝20.6Hz）
3.57（d，6H，J＝11Hz）
2.54（s，3H）
Mass spectrum: CI m/e371(M+H) +
IR:(CHCl 3Solution)
3016，2956，2857，1617，1521，1500，1245，1188，1162，1071，1047，834cm -1.
C.(E)-(2-(1-(4-fluorophenyl)-3-methyl-2-naphthyl) phosphonic acids mono-methyl vinyl)
In argon gas with the vinylphosphonate of B part (9.72 mmoles stir in the 3.60 gram) Yu dioxs (23.5 milliliters), and with 1N LiOH(23.32 mmole, 23.32 milliliters) processing.This reaction mixture heated 1 hour in 75 ℃ of oil baths.Then, this reaction mixture is chilled to room temperature, the vacuum removal solvent.The gained resistates is with 15 milliliters of H 2O dilution is chilled to 0 ℃, and uses the 5%HCl(aqueous solution) be acidified to pH=1.Water layer extracts 4 times with EtOAC.Merge organic extract liquid, use MgSO 4Drying is filtered, and concentrates, and with benzene azeotropic 2 times, vacuum-evaporation obtains 3.38 gram (9.48 mmoles, productive rate 98%) title phosphonate monoesters, is the peachiness solid.
TLC: silica gel, 10: 1: 1 CH of pMA Rf=0.41 2Cl/MeOH/CH 3CO 2H
1H NMR：（270MHz，CDCl 3）
δ 7.76（d，1H，J＝8.4Hz）
7.68（s，1H）
7.47-7.09（m，8H）
5.61（dd，1H，J＝18.47Hz，J＝20.58Hz）
3.48（d，3H，J＝10.96Hz）
2.52（s，3H）
Mass spectrum: FAB m/e 357(M+H) +
IR:(CHCl 3Solution)
3025，3008，2951，1614，1605，1511，1494，1235，1210，1188，1158，1050，987，833cm -1.
D.(E)-and 4-((2-(1-(4-fluorophenyl-3-methyl-2-naphthyl) vinyl) methoxyl group phosphinyl)-3-ketobutyric acid, methyl esters
In argon gas with the phosphonate monoester (9.12 mmoles, 3.29 grams) of C part in anhydrous CH 2Cl 2Stir in (60 milliliters), and drip trimethyl silyl diethylamide (TMSDEA) (18.24 mmoles, 2.65 grams, distilled by 3.45 milliliters) processing (10 minutes).This reaction mixture at room temperature stirred 1.5 hours.Remove volatilization component (entering in the argon gas) on rotatory evaporator, resistates was taken out under high vacuum 40 minutes.Then, in argon gas with this resistates in anhydrous CH 2Cl 2Stir in (25 milliliters).This solution is chilled to 0 ℃, handles with 2 dry DMF, then drips (15 minutes) oxalyl chloride (10.94 mmoles, 1.39 grams, 0.955 milliliter).This reaction mixture stirred 20 minutes down at 0 ℃, heated to room temperature then and stirred 1 hour.Remove the volatilization component as stated above and take out this resistates.At last, in argon gas with this resistates in anhydrous THF(25 milliliter) in stir, be chilled to-78 ℃ and remain on-78 ℃, simultaneously this solution transferred in the dropping funnel by sleeve pipe, drip (20 minutes) then in-78 ℃ methyl acetoacetates two anionic THF solution.This two anion solutions produces by following manner: with the NaH(13.22 mmole, 0.317 gram, 0.397 gram, 80% mineral oil suspension) with pentane washing once, dry in argon gas stream, then under argon gas in anhydrous THF(20 milliliter) in stirring.This suspension is chilled to 0 ℃, and drips methyl acetoacetate (12.31 mmoles, 1.43 grams, 1.33 milliliters) in anhydrous THF(10 milliliter) in solution-treated (10 minutes).The gained clear solution stirred 20 minutes down at 0 ℃, dripped the n-BuLi(11.40 mmole then, 4.56 milliliters 2.5M hexane solution) processing (10 minutes).The gained yellow solution stirred 45 minutes down at 0 ℃, was chilled to-78 ℃ then, and-78 ℃ of THF solution of formed phosphonyl chloride are handled above dripping.After adding, this reaction mixture stirred 45 minutes down at-78 ℃.Then, use saturated NH 4The Cl(aqueous solution) (50 milliliters) stop this reaction, heat to room temperature, use H 2The O(50 milliliter) and the EtOAC(50 milliliter) dilution.Water layer NaHCO 3CH is used in (aqueous solution) extraction 3 times 2Cl 2Extraction once.Merge organic extract liquid, use saturated NaHCO 3(aqueous solution) washing 3 times with the salt water washing once, is used MgSO 4Drying is filtered and vacuum-evaporation, obtains 4.0 gram rust foams.Carry out preliminary purification by dodging formula chromatography (post of 40 milliliters of diameters, 20: 1Merck silica gel, 100%EtOAC elutriant, 2 "/minute flow velocity), obtain the not too pure title ketone-phosphinate of 2.0 grams, be orange.Follow-up chromatography (post of 30 mm dias, 25: 1Merck silica gel, 95%EtOAC/ hexane elutriant, 2 "/minute flow velocity), obtain 1.95 gram (4.29 mmoles, productive rate 47%) title ketone phosphinates, be orange foams.
TLC: silica gel, PMA R f=0.29 100% EtOAC
1H NMR：（270MHz，CDCl 3）
δ 7.78-7.13(aromatic hydrocarbons, alkene, 10H)
5.62（dd，1H，J＝17.93Hz，J＝25.84Hz）
3.71（s，3H）
3.63（s，2H）
3.48（d，3H，J＝11.6Hz）
3.14&3.13（2 x d，2H，J＝18.46Hz）
2.44（s，3H）
Mass spectrum: CI m/e 455(M+H) +
IR: film
1749，1717，1623，1614，1604，1511，1328，1223，1159，1031，834cm -1
E.(E)-4-((2-(1-(4-fluorophenyl)-3-methyl-2-naphthyl) vinyl) methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl esters
In argon gas with the ketone phosphinate (2.82 mmoles, 1.28 grams) of D part in anhydrous THF(12 milliliter) in stirring.This solution is chilled to 0 ℃, and uses NaBH 4(2.82 mmoles, 0.107 gram) are handled, then drip methyl alcohol (2.45 milliliters, with 4
Figure 881036994_IMG207
Molecular sieve drying).This reaction mixture stirred 1 hour down at 0 ℃, used 2.5 milliliters of acetone stopped reaction then.Add 1.3 gram CC-4 silica gel (Mallinckrodt) and stir this reaction mixture.Simultaneously it is heated to room temperature.At last, filter this suspension,, use CH with EtOAC washing 2 times by the sintered glass funnel 2Cl 2Wash 2 times.This filtrate of vacuum-evaporation obtains the orange foams of 1.3 grams, produces crystallization when adding EtOAC.This product is by sudden strain of a muscle formula chromatography (post of 30 mm dias, 30: 1Merck silica gel, 3%MeOH/CH 2Cl 2Elutriant, 2 "/minute flow velocity) carry out purifying.Merge the product fraction, evaporation with benzene azeotropic once, obtains 0.653 gram (1.43 mmoles, productive rate 51%) title hydroxyl phosphinate, is light yellow solid.This pure products is with 7: the development of 3EtOAC/ hexane, obtain 0.516 gram hydroxyl phosphinate, and be white solid.m.p.＝132～134.5℃
TLC: silica gel, PMA R f=0.38 4% MeOH/CH 2Cl 2
1H NMR：（270MHz，CDCl 3）
δ 7.79-7.16(aromatic hydrocarbons, alkene, 10H)
5.59（2 x dd，1H，J＝17.94Hz，J＝24.27Hz）
4.35&4.24（2 x m，1H）
3.70（s，3H）
3.49&3.47（2 x d，3H，J＝11Hz）
2.58-2.53（m，2H）
2.54&2.53（2 x s，3H）
2.01-1.74（m，2H）
Mass spectrum: CI m/e 457(M+H) +
IR：（KBr）
3422-3382，3062，3051，2951，2926，2913，1738，1613，1604，1511，1494，1457，1438，1399，1373，1330，1311，1307，1286，1220，1194，1177，1160，1092，1077，1035，883，833cm -1.
F.(E)-4-((2-(1-(4-fluorophenyl)-3-methyl-2-naphthyl) vinyl) hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
In argon gas with the diester of E part (1.1 mmoles, stir in the 0.50 gram) Yu diox (10.45 milliliters) and with 1N LiOH(3.3 mmole, 3.3 milliliters) processing.This reaction mixture heated 45 minutes in 70 ℃ of oil baths.The gained white slurry is dissolved in～100 milliliter 9: 1H 2Among the O/MeOH, and rotation is evaporated to dried under 35 ℃.This white solid was taken out under high vacuum 1 hour, and then was dissolved in 100 milliliter 9: 1H 2Among the O/MeOH, and rotary evaporation is to～8 ml volumes.This muddy solution directly is added to the HP-20 chromatographic column, and (2.5 centimetres of 17.5 cm x are used H 2The O balance) goes up and with 250 milliliters of H 2The O wash-out is then with 45: 55MeOH/H 2The O wash-out.Collected fraction (～10 milliliters) in per 1.3 minutes.Merge the product fraction,, be dissolved in H again at 35 ℃ of following rotary evaporations 2O, P is used in lyophilize 16 hours 2O 5Under high vacuum, took out 16 hours, and obtained the title dilithium salt of 0.449 gram, 1.02 mmoles, productive rate 93%, be white lyophilized products.
TLC: silica gel, PMA Rf=0.49 7: 2: 1(n-C 3H 7OH/NH 4OH/H 2O)
1H NMR：（400MHz，D 2O）
δ 7.73（d，1H，J＝8.06Hz）
7.64（s，1H）
7.43-7.39（m，1H）
7.25-7.13（m，4H）
7.05-6.95（m，3H）
5.62（dd，1H，J＝17.96Hz，J＝21.2Hz）
2.43（s，3H）
2.38（dd，1H，J＝4.03Hz，J＝15.39Hz）
2.22（dd，1H，J＝9.16Hz，J＝15.39Hz）
1.59-1.51（m，2H）
Mass spectrum: FAB m/e 429(M+H) +, 435(M+Li) +,
441（M+2Li） +
IR：（KBr）
3431（br），1603，1593，1511，1494，1423，1221，1158，1050cm -1
Ultimate analysis calculated value: C 23H 20FO 5PLi 20.87 mole H 2O
M.W.＝455.94：C，60.60;H，4.80;F，4.17;P，6.79
Measured value: C, 60.60; H, 4.73; F, 4.24; P, 6.82
Embodiment 61
(S)-4-((2-(1-(4-fluorophenyl)-3-methyl-2-naphthyl) ethyl) hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
A.(S)-and 3-(((1, the 1-dimethyl ethyl) diphenylmethyl silylation) oxygen)-4-((2-(1-(4-fluorophenyl)-3-methyl-2-naphthyl) ethynyl) methoxyl group phosphinyl) butyric acid, methyl esters
The acetylene phosphinate (0.974 mmole, 0.675 gram) of embodiment 59J part is dissolved in the methyl alcohol (14.3 milliliters).Argon gas was passed through this solution bubbling 10 minutes, adds the 10%Pd/C(0.270 gram then), this reaction mixture is at 40Psi H 2Following shake 24 hours on the Pa Er hydrogenator.Filter this reaction mixture by Celite pad, use methanol wash, vacuum-evaporation filtrate obtains the white foam body.This product obtains 0.556 gram (0.798 mmole, productive rate 82%) saturated phosphinate of title by sudden strain of a muscle formula chromatography (post of 50 milliliters of diameters, 4.5 " Merck silica gel, 70%EtOAC/ hexane elutriant, 2 "/minute flow velocity), is the white foam body.This post methanol-eluted fractions obtains 0.101 other gram (0.145 mmole, 15%) product.
TLC: silica gel, pMA Rf=0.24 60%EtOAC/ hexane
1H NMR：（270MHz，CDCl 3）
δ 7.78-7.14(aromatic hydrocarbons, 19H)
4.44（m，1H）
3.61（s，3H）
3.35&3.23（2 x d，3H，J＝10.6Hz）
2.92-2.83（m，1H）
2.63-2.54（m，3H）
2.21-1.27（m，4H）
2.45&2.42（2 x s，3H）
1.00（s，9H）
Mass spectrum: CI m/e 697(M+H) +
IR:(CHCl 3Solution)
3028，3019，3007，2997，2953，2933，2859，1735，1510，1497，1472，1463，1439，1428，1378，1364，1314，1236，1197，1157，1142，1112，1091，1073，1065，1043，823cm -1.
B.(S)-4-((2-(1-(4-fluorophenyl)-3-methyl-2-naphthyl) ethyl) methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl esters
In argon gas with silyl ether (0.775 mmole of A part, 0.540 gram) in 9.45 milliliters of anhydrous THF, stir, and with Glacial acetic acid (3.10 mmoles, 0.186 gram, 0.177 milliliter), then dripping tetrabutylammonium fluoride (2.33 mmoles, 2.1 milliliters 1.1M THF solution) handles.This reaction mixture at room temperature stirred 16 hours.This reaction mixture is with 30 milliliters of frozen water stopped reaction, and dilutes with EtOAC.Water layer extracts 3 times with EtOAC.Merge organic extract liquid, use saturated NaHCO 3(aqueous solution) washing once with the salt water washing once, is used MgSO 4Drying is filtered and vacuum-evaporation.By dodging formula chromatography (post of 40 mm dias, 6 " Merck silica gel, 4%MeOH/CH 2Cl 2Elutriant, 2 "/minute flow velocity) carry out preliminary purification, obtain 0.40 gram white solid.This solid is developed with 100% hexane, filters also and takes out under high vacuum 8 hours, obtains 0.317 gram (0.691 mmole, productive rate 89%) title hydroxyl phosphinate, is white solid, m.p.=120～122 ℃.
TLC: silica gel Rf=0.12 2% MeOH/CH 2Cl 2
1H NMR：（270MHz，CDCl 3）
δ 7.76（d，1H，J＝7.9Hz）
7.69（s，1H）
7.42-7.16（m，7H）
4.42&4.26（2 x m，1H）
3.92&3.84（2 x d，1H，J＝3.16Hz）
3.72（s，3H）
3.58&3.54（2 x d，3H，J＝3.69Hz）
2.89-2.76（m，2H）
2.56（s，3H）
2.63-2.41（m，2H）
1.92-1.61（m，4H）
Mass spectrum: CI m/e459(M+H) +
IR：（KBr）
3428（br），3287（br），3064，3050，3017，2989，2952，2921，1737，1603，1510，1497，1458，1438，1234，1221，1191，1175，1159，1042，826cm -1.
C.(S)-4-((2-(1-(4-fluorophenyl)-3-methyl-2-naphthyl) ethyl) hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
(0.687 mmole stirs in the 0.315 gram) Yu diox (6.9 milliliters) with B diester partly in argon gas.This solution 1N LiOH(2.06 mmole, 2.06 milliliters) handle.This reaction mixture heated 45 minutes in 70 ℃ of oil baths.This reaction mixture is chilled to room temperature.Remove solvent at 35 ℃ of following rotary evaporations, the gained white solid was taken out under high vacuum 1 hour.Then, this solid is dissolved in～8 milliliters of distillation H 2Among the O and be added to the Hp-20 chromatographic column (2.5 centimetres of 16 cm x are used H 2The O balance) on.This post is with 250 milliliters of H 2The O wash-out is then with 45: 55 MeOH/H 2The O wash-out.Collected fraction (～10 milliliters) in per 1.4 minutes.Merge product fraction (37～47), evaporate on rotatory evaporator under 35 ℃, p is used in lyophilize 16 hours 2O 5Under high vacuum, took out 8 hours, and obtained 0.286 gram (0.647 mmole, productive rate 94%) title dilithium salt, be white lyophilized products.
TLC: silica gel, pMA Rf=0.42 7: 2: 1
（n-C 3H 7OH/NH 4OH/H 2O）
1H NMR：（400MHz，D 2O）
δ 7.82（d，1H，J＝8.06Hz）
7.76（s，1H）
7.46-7.42（m，1H）
7.30-7.25（m，3H）
7.18-7.13（m，3H）
4.06（m，1H）
2.72-2.66（m，2H）
2.54（s，3H）
2.34（dd，1H，J＝4.4Hz，J＝15.22Hz）
2.22（dd，1H，J＝8.43Hz，J＝15.02Hz）
1.59-1.51（m，2H）
1.44-1.39（m，2H）
Mass spectrum: FAB m/e443(M+H) +
IR：（KBr）
3451-3426（br），3151，3124，1620，1593，1509，1439，1422，1403，1218，1159，1050cm -1.
Ultimate analysis calculated value: C 25H 22FO 5PLi 20.60 mole H 2O
M.W.＝453.09：C，60.96;H，5.16;F，4.19;P，6.83
Measured value: C, 60.96; H, 5.29; F, 4.12; P, 6.82
Embodiment 62
4-((3-(4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)-the 2-yl) propyl group) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
A.3-(4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)-the 2-yl)-2-vinylformic acid, ethyl ester
In argon gas that sodium hydride (4.96 mmoles, 0.119 gram, 80% mineral oil suspension of 0.149 gram) is dry once and under argon gas stream with hexane wash.Then, in argon gas with this NaH in anhydrous THF(9.1 milliliter) in stir.This suspension be chilled to 0 ℃ and drip the phosphonoacetic acid triethyl (4.96 mmoles, 1.11 the gram, 0.983 milliliter) in anhydrous THF(2.2 milliliter) in solution-treated (5 minutes).The gained clear solution stirred 15 minutes down at 0 ℃, heated to room temperature then and stirred 30 minutes.At last, drip the aldehyde (4.13 mmoles, 1.0 grams) of (8 minutes) embodiment 1C part in anhydrous THF(2.5 milliliter) in solution.This reaction mixture at room temperature stirred 1 hour.This mixture H 2The O stopped reaction, water layer is used Et with EtOAC extraction 2 times 2O extraction 2 times.Merge organic extract liquid, with the salt water washing once, use MgSO 4Drying is filtered and vacuum-evaporation.This product carries out purifying (post of 50 mm dias, 6 " Merck silica gel, 6%EtOAC/ hexane elutriant, 2 "/minute flow velocity) by dodging the formula chromatography, obtains the 1.19(3.79 mmole, productive rate 92%) title contains the ester of ethene structure, is light yellow foams.
TLC: silica gel, PMA Rf=0.22 4% EtOAC/ hexane
1H NMR（270MHz，CDCl 3）
δ 7.64（d，1H，J＝16.35Hz）
7.09-6.93（m，5H）
5.81（d，1H，J＝16.35Hz）
4.17（q，2H，J＝7.12Hz）
2.42（s，3H）
2.33（s，3H）
2.28（s，3H）
1.25（t，3H，J＝7.12Hz）
Mass spectrum: CI m/e 313(M+H) +
B.4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)-the 2-butyric acid, ethyl ester
The ester that contains the ethene structure (3.68 mmoles, 1.15 grams) of A part is dissolved in anhydrous EtOH(36 milliliter) in.Argon gas passed through this solution bubbling 10 minutes.Add the 10%pd/C(230 milligram) and with H 2(gas) passed through this solution bubbling 10 minutes.This reaction mixture is at H 2Stirred 2 hours in the atmosphere.This reaction mixture dilutes with EtOH, and by in 60 milliliters of sintered glass funnels (1 ")/2 Celite pad filters.This Celite pad washs with EtOH.Vacuum-evaporation filtrate obtains 1.12 gram (3.56 mmoles, productive rate 97%) title saturated ester, is white solid.
TLC: silica gel, PMA Rf=0.29 5%EtOAC/ hexane
1H NMR（270MHz，CDCl - 3）
δ 7.09-6.97（m，4H）
6.84（s，1H）
4.06（q，2H，J＝7.12Hz）
2.90-2.84（m，2H）
2.37（s，3H）
2.30（2 x s，6H）
2.32-2.27（m，2H）
1.20（t，3H，J＝7.12Hz）
Mass spectrum: CI m/e 315(M+H) +
C.4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)-the 2-propyl alcohol
In argon gas with lithium aluminum hydride (3.5 mmoles, 0.133 gram) in anhydrous Et 2The O(3.5 milliliter) stirs in.This suspension is chilled to 0 ℃, and drips B ester (3.5 mmoles, 1.1 grams) partly in anhydrous Et 2The O(3.5 milliliter) solution-treated in (8 minutes).This reaction mixture stirred 15 minutes down at 0 ℃, heated to room temperature then and stirred 45 minutes.This mixture is chilled to 0 ℃ again and also drips 0.133 milliliter of H successively 2O, 0.133 milliliter of 15%NaOH, last 0.399 milliliter of H 2O handles.This suspension was heated to room temperature with 30 minutes.Filter gained white powder solid, and use anhydrous Et 2The O washing.Concentrated filtrate, with benzene azeotropic once, vacuum-evaporation then obtains 0.950 gram alcohol, with it by the sudden strain of a muscle formula chromatography (post of 50 mm dias, 6 " Merck silica gel; 35% EtOAC/ hexane elutriant, 2 "/minute flow velocity) purifying, obtain 0.906 gram (3.33 mmoles, productive rate 95%) title alcohol is colorless oil.TLC: silica gel, PMA Rf=0.18 20% EtOAC/ hexane
1H NMR（270MHz，CDCl 3）
δ 7.08-6.93（m，4H）
6.82（s，1H）
3.45-3.40（m，2H）
2.60-2.54（m，2H）
2.34（s，3H）
2.28（2 x s，6H）
1.63-1.52（m，2H）
Mass spectrum: CI m/e 273(M+H) +
Bromopropyl)-4 D.2-(3-'-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)
With triphenylphosphine (10.1 mmoles, 2.65 gram) in anhydrous THF(27.5 milliliter) in solution be chilled to 0 ℃, and drip carbon tetrabromide (10.71 mmoles, 3.55 grams) in anhydrous THF(5.5 milliliter) in solution handle.Gained Huang/white slurry stirred 2 hours down at 0 ℃.The alcohol (4.04 mmoles, 1.1 grams) that drips the C part in this mixture is in anhydrous THF(8.2 milliliter) in solution handle.This reaction mixture stirred 1 hour down at 0 ℃, heated to room temperature then and stirred 16 hours.This reaction mixture Et 2The O dilution is filtered by the sintered glass funnel, uses Et 2The O washing precipitate.Filtrate with the salt water washing is once used MgSO 4Drying is filtered and vacuum-evaporation.This product obtains 1.35 gram (4.05 mmoles, productive rate 100%) title bromides by sudden strain of a muscle formula chromatography (post of 50 mm dias, 6 " Merck silica gel, 2%EtOAC/ hexane elutriant, 2 "/minute flow velocity) purifying, is light yellow oil.
TLC: silica gel, PMA Rf=0.22 100% hexane
1H NMR（270MHz，CDCl 3）
δ 7.07-6.99（m，4H）
6.82（s，1H）
3.22（m，2H）
2.69-2.63（m，2H）
2.36（s，3H）
2.30（s，3H）
2.28（s，3H）
1.90-1.80（m，2H）
Mass spectrum: CI m/e 235(M+H) +
E. (3-(4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)-the 2-yl) propyl group) phosphonic acids, dimethyl ester
Bromide (3.88 mmoles, 1.3 grams) with the D part in argon gas stirs in trimethyl phosphite (38.8 milliliters).This reaction mixture reflux 36 hours in 135 ℃ of oil baths.Remove excessive (CH by short-path distillation 3O) 3P, resistates was taken out under high vacuum 1 hour at 100 ℃.The gained yellow oil is dodged formula chromatography purification (post of 50 mm dias, 6 " Merck silica gel, 85%EtOAC/ hexane stream takes off liquid, 2 "/minute flow velocity), obtains 1.13 gram (3.10 mmoles, productive rate 80%) title dimethyl phosphonates, is colorless oil.
TLC: silica gel, pMA, Rf=0.28 100%EtOAC
1H NMR（270MHz，CDCl 3）
δ 7.08-6.97（m，4H）
6.81（s，1H）
3.65（d，6H，J＝11Hz）
2.63-2.56（m，2H）
2.34（s，3H）
2.30（2 x s，3H）
2.28（s，3H）
1.68-1.50（m，4H）
Mass spectrum: CI m/e 365(M+H) +
F. (3-(4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)-the 2-yl) the propyl phosphonous acid mono-methyl
(3.43 mmoles stir in the 1.25 gram) Yu dioxs (8.23 milliliters) with E phosphonic acid ester partly in argon gas.This solution 1N LiOH(5.15 mmole, 5.15 milliliters) handle, and in 95 ℃ of oil baths, heat.After 1 hour, add 3.43 mmole LiOH again, this reaction mixture reheat to 95 ℃ 3.5 hours.This reaction mixture is chilled to room temperature.The vacuum removal solvent.The white solid resistates is with 25 milliliters of H 2O dilution, this slurry be chilled to 0 ℃ and use the 5%HCl(aqueous solution) be acidified to pH=1.Water layer extracts 4 times with EtOAC.Merge organic extract liquid, use MgSO 4Drying is filtered concentrated filtrate.Resistates and benzene azeotropic 2 times, gained thickness oily matter was taken out under the high-altitude 4 hours, obtained 1.18 gram (3.37 mmoles, productive rate 98%) phosphonic acids mono-methyls, was yellow oil.
TLC: silica gel, pMA, Rf=0.46 10: 1: 1
CH 2cl 2/MeOH/CH 3COOH
1H NMR（270MHz，CDCl 3）
δ 7.06-6.95（m，4H）
6.81（s，1H）
3.56（d，3H，J＝11Hz）
2.62-2.53（m，2H）
2.32（s，3H）
2.27（2 x s，6H）
1.69-1.48（m，4H）
Mass spectrum: FAB m/e 351(M+H) +
G.4-((3-(4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)-the 2-yl) propyl group) the methoxyl group phosphinyl)-the 3-ketobutyric acid, methyl esters
In argon gas with the phosphonate monoester (3.22 mmoles, 1.13 grams) of F part in anhydrous CH 2Cl 2Stir in (12.9 milliliters).Drip the TMSDEA(6.44 mmole toward this solution, 0.918 gram, 1.20 milliliters of new distillatory) processing (8 minutes).This solution at room temperature stirred 1.5 hours.Vacuum removal volatiles (entering in the argon gas).Resistates and 70 milliliters of dry-out benzene azeotropic once, vacuum-evaporation (entering in the argon gas).At last, resistates was taken out under high vacuum 50 minutes.Then, with resistates under argon gas in anhydrous CH 2Cl 2Stir in (12.9 milliliters).Add two dry DMF, this solution is chilled to 0 ℃ and drip oxalyl chloride (3.70 mmoles, 0.470 gram, 0.323 milliliter) and handle (8 minutes).This reaction mixture stirred 20 minutes down at 0 ℃, heated to room temperature then and stirred 1-3/4 hour.Remove volatiles as mentioned above, make resistates and benzene azeotropic, and under high vacuum, take out.Then with this rust oily matter under the argon gas in anhydrous THF(9.0 milliliter) in stir.This solution is chilled to-78 ℃ and remain under-78 ℃, simultaneously with its dropping (20 minutes) in anionic-78 ℃ THF solution of the methyl acetoacetate that produces in the following manner two: with sodium hydride (4.85 mmoles, 0.116 gram, 0.145 restrain 80% mineral oil dispersion) with hexane wash once, and dry under argon gas stream.Then with this solid under the argon gas in anhydrous THF(7.1 milliliter) in stir, and this suspension is chilled to 0 ℃.Drip (8 minutes) methyl acetoacetate (4.36 mmoles, 0.506 gram, 0.471 milliliter) in anhydrous THF(3.6 milliliter) in solution, the gained clear solution stirred 45 minutes down at 0 ℃.Then, drip the n-BuLi(4.04 mmole toward this reaction mixture, 1.62 milliliters 2.5M hexane solution Aldrich) is handled (10 minutes).The gained yellow solution stirred 35 minutes down at 0 ℃, was chilled to-78 ℃ then and also dripped-78 ℃ the phosphonyl chloride THF solution-treated (20 minutes) that forms above.This reaction mixture stirred 1 hour down at-78 ℃, used saturated NH then 4The cl(aqueous solution) (45 milliliters) stopped reaction, and heat to room temperature.This mixture H 2The O(45 milliliter) and EtOAC dilution.Water layer extracts 4 times with EtOAC.Merge organic extract liquid, use saturated NaHCO 3(aqueous solution) washing once with the salt water washing once, is used MgSO 4Drying is filtered and vacuum-evaporation, obtains 2.0 gram rust oily matter.This product is by sudden strain of a muscle formula chromatography (post of 40 mm dias, 35: 1Merck silica gel, 100%EtOAC～5%MeOH/CH 2Cl 2Elutriant, 2 "/minute flow velocity) separate, obtain 0.220 gram (0.491 mmole, productive rate 15%) title β-oxo phosphinate, be rust oily matter.
TLC: silica gel, PMA Rf=0.19 100%EtOAC
1H NMR（270MHz，CDCl 3）
δ 7.08-6.98（m，4H）
6.81（s，1H）
3.73（s，3H）
3.65（d，3H，J＝11Hz）
3.64（s，2H）
3.10（dd，2H，J＝5.27Hz，J＝17.41Hz）
2.67-2.57（m，2H）
2.35（s，3H）
2.30&2.28（2 x s，3H）
2.29（s，3H）
1.72-1.56（m，4H）
Mass spectrum: CI m/e 449(M+H) +
H.4-((3-(4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)-the 2-yl) propyl group) the methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl esters
In argon gas with the β-oxo phosphinate (0.223 mmole, 0.10 gram) of G part in anhydrous THF(1.9 milliliter) in stirring.This solution is chilled to 0 ℃, uses NaBH then 4(0.223 mmole, 0.008 gram) handled, and then drips the MeOH(0.194 milliliter, with 4
Figure 881036994_IMG208
Molecular sieve drying) handles.This reaction mixture stirred 1 hour down at 0 ℃, added acetone (0.194 milliliter) then, then added 0.10 gram CC-4 silica gel (Mallinckrodt) reaction is stopped.This suspension is stirred, heat simultaneously, filter by the sintered glass funnel then to room temperature.Wash this silica gel with EtOAC.Vacuum-evaporation filtrate obtains the golden oily matter of 0.108 gram.By dodging formula chromatography (post of 10 mm dias, 35: 1Merck silica gel, 4%MeOH/CH 2Cl 2Elutriant, 2 "/minute flow velocity) two kinds of reaction product of separation.Obtain desired title beta-hydroxy phosphinate, productive rate is the 58%(0.058 gram, 0.129 mmole), be light yellow oil.Also obtain 0.019 gram (0.043 mmole, productive rate 20%) 1,3 butylene glycol phosphinate.
TLC: silica gel, PMA Rf=0.19 3.5%
MeOH/CH 2Cl 2
1H NMR（270MHz，CDCl 3）
δ 7.08-6.98（m，4H）
6.82（s，1H）
4.44&4.32（2 x m，1H）
3.63&3.62（2 x d，3H，J＝10.55Hz）
3.70（s，3H）
2.65-2.50（m，4H）
2.35（s，3H）
2.30（2 x s，3H）
2.29（s，3H）
1.89-1.76（m，2H）
1.71-1.59（m，4H）
Mass spectrum: CI m/e 451, (M+H) +
I.4-((3-(4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)-the 2-yl) propyl group) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
In argon gas with the diester of H part (0.122 mmole stirs in the 0.055 gram) Yu diox (2 milliliters), and with 1N LiOH(0.366 mmole, 0.366 milliliter) processing.This reaction mixture heated 45 minutes in 80 ℃ of oil baths.This reaction mixture is chilled to room temperature and removes solvent on rotatory evaporator.The gained yellow solid was taken out under high vacuum 2 hours, obtained the title dilithium salt, was yellow solid.
TLC: silica gel, PMA Rf=0.29 8: 1: 1
CH 2Cl/MeOH/CH 3CO 2H
1H NMR（270MHz，D 2O）
δ 7.08-7.05（m，4H）
6.80（s，1H）
4.13（m，1H）
2.54-2.47（m，2H）
2.38-2.28（m，2H）
2.30（s，3H）
2.22（s，3H）
2.20（s，3H）
1.59-1.50（m，2H）
1.42-1.29（m，4H）
Embodiment 63
(1S-(1＜a(R *), 2＜a, 4a＜b, 8＜b, 8a＜a))-4-((2-(8-(2,2-dimethyl-1-oxo butoxy) decahydro-2-methyl isophthalic acid-naphthyl) ethyl) hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
A. (1S-(1＜a, 2＜a, 4a＜b, 8＜b, 8a＜a))-8-(((1, the 1-dimethyl ethyl) dimetylsilyl) oxygen)-1,2,4a, 5,6,7,8,8a-octahydro-2-methyl isophthalic acid-naphthalene methyl alcohol
To the anhydrous Et under 0 ℃ (ice bath) 2The O(5 milliliter) adds lithium aluminum hydride (132 milligrams, 1 molar equivalent) in, then drip (1S-(1＜a, 2＜a, 4a＜b, 8＜b, 8a＜a))-8-(((1, the 1-dimethyl ethyl) dimetylsilyl) oxygen)-1,2,4a, 5,6,7,8,8a-octahydro-2-methyl isophthalic acid-2-methyl naphthoate (people such as R.L.Funk, Tetrahedron Lett.25,1655(1984)) (1.175 grams, 3.47 mmoles) are in anhydrous Et 2The O(5 milliliter) solution in, gained grey suspension at room temperature stir in argon gas and spend the night.This mixture is by dripping H continuously 215%NaOH(130 microlitre) and H the O(130 microlitre), 2The O(390 microlitre) stopped reaction.By anhydrous MgSO 4And following filling diatomite filtration is removed sedimentary salt.Vacuum-evaporation obtains the limpid oily matter of 1.112 grams, and it is carried out purifying by dodging the formula chromatography on silica gel, with (95: 5) hexane/EtOAC wash-out, obtain 902 milligrams (85.7%) desired title alcohol, be limpid oily matter, it places post crystallization, m.p.=79～81 ℃
TLC(9: 1) hexane-EtOAC, Rf=0.21
Ultimate analysis calculated value: C 18H 34O 2Si:C, 69.61; H, 11.04
Measured value: C, 69.64; H, 11.04
1H NMR（CDCl 3）
δ 0.00（s，6H）
0.82（s，9H）
0.83（d，3H）
0.94-1.05（m，2H）
1.18（s，1H）
1.2-1.42（m，2H）
1.67（m，3H）
1.89（m，1H）
2.25﹠amp; 2.37(2H, 2 multiplets)
3.42（bt，1H）
3.80（dd，1H）
3.93（bs，1H）
5.29（d，1H）
5.48（dq，1H）ppm.
B. (1s-(1＜a, 2＜a, 4a＜b, 8＜b, 8a＜a))-8-(((1, the 1-dimethyl ethyl) dimetylsilyl) oxygen)-1,2,4a, 5,6,7,8,8a-octahydro-2-methyl isophthalic acid-naphthaldehyde
With Dess-Martin periodo alkane (Periodinane) (895 milligrams, 2.11 mmoles) in anhydrous CH 2Cl 2The anhydrous t-C of solution in (6 milliliters) 4H 9The OH(200 microlitre) handles, and this white suspension was at room temperature stirred 15 minutes in argon gas.Dripped preceding step alcohol (596 milligrams, 1.92 mmoles) in anhydrous CH with 5 minutes 2Cl 2Solution in (6 milliliters), this mixture at room temperature stirred 20 minutes in argon gas.This mixture is added to Sulfothiorine (2.12 gram) in 1.0N NaHCO 3In the solution in (12 milliliters), and the gained mixture stirred all dissolve up to all solids.The saturated NaHCO of organic phase 3, H 2Anhydrous Na is used in O and salt water washing then 2SO 4Dry also vacuum-evaporation obtains 1.005 gram colorless oil.This crude product and another crude product in a small amount merge (1.306 grams altogether), carry out purifying by dodging the formula chromatography then on silica gel, with (98: 2) hexane-EtoAC wash-out.Vacuum-evaporation product fraction obtains 667 milligrams (75.7%) desired title aldehyde, is colorless oil.
TLC:(7: 3) hexane-Et 2O, R angle=0.70PMA
1H NMR（CDCl 3）：
δ 0.07（s，3H）
0.00（s，3H）
0.85（s，9H）
0.89（d，3H）
0.93-1.10（m，2H）
1.38-1.52（m，2H）
1.58-1.78（m，4H）
2.31（m，1H）
2.66（m，1H）
2.78（m，1H）
4.30（s，1H）
5.40（d，1H）
5.50（m，1H）
9.74（d，1H）
C. (1s-(1＜a, 2＜a ,-4a＜b, 8＜b, 8a＜a))-1-(2, the 2-dibromo vinyl)-8-(((1, the 1-dimethyl ethyl) dimetylsilyl) oxygen)-1,2,4a, 5,6,7,8,8a-octahydro-2-methylnaphthalene
The aldehyde (667 milligrams, 2.16 mmoles) of past B part and triphenylphosphine (1.7 grams, 6.48 mmoles) are in anhydrous CH 2Cl 2Drip the CH of carbon tetrabromide (1.7 grams, 6.48 mmoles) in the solution of-15 ℃ (salt/ice bath) in (10 milliliters) 2Cl 2(5 milliliters) solution was handled 5 minutes, should stir 30 minutes in argon gas under-15 ℃ by dark red brown mixture, stirred 2 hours down at 0 ℃, at room temperature stir at last and spend the night, this mixture is chilled to 0 ℃ again, adds (567 milligrams of triphenylphosphines again, 216 mmoles) handle, then use CBr 4(358 milligrams, 1.08 mmoles) are handled, and at room temperature stir then 4 hours.The saturated NaHCO of this mixture 3(10 milliliters) stopped reaction is used CH 2Cl 2Dilution is filtered organic phase by sintered glass, uses saturated NaHco 3With the salt water washing, use anhydrous Na 2So 4Dry also vacuum-evaporation obtains 3.578 gram brown solid.Crude product carries out purifying with silica gel by dodging the formula chromatography, with pure hexane wash-out.The evaporate fraction obtains 677 milligrams (67.3%) pure title sym-dibromoethane based compound, is colorless oil.
TLC(9: 11 hexanes-acetone, Rf=0.73UV+PMA)
1H NMR（CDCl 3）
δ 0.08﹠amp; 0.10(2 singlet 6H)
0.85（d，3H）
0.90（s，9H）
0.98（m，2H）
1.25-2.52（m，5H）
1.74（m，1H）
1.82（m，1H）
2.39（m，1H）
2.56（m，1H）
2.66（m，1H）
3.95（s，1H）
5.48（d，1H）
5.52（m，1H）
6.37（d，1H）ppm.
D. (1s-(1＜a, 2＜a, 4a＜b, 8＜b, 8a＜a))-8-(((1, the 1-dimethyl ethyl) dimetylsilyl) oxygen)-1-ethynyl-1,2,4a, 5,6,7,8,8a-octahydro-2-methylnaphthalene
Toward (495 milligrams of C sym-dibromoethane based compounds partly, 1.07 mmole) in anhydrous THF(6 milliliter) in the solution of-78 ℃ (in ice/acetone) in drip (1.34 milliliters of 1.6M n-BuLi hexane solutions, 2.14 mmole) handled 5 minutes, this clear, colorless mixture stirred 30 minutes in argon gas under-78 ℃.This mixture passes through to add saturated NH down at-78 ℃ 4The Cl(5 milliliter) stopped reaction heats it to room temperature, and with the EtOAC dilution, anhydrous Na is used in organic phase salt water washing 2SO 4Dry also vacuum-evaporation, obtaining 291 milligrams (89.6%) thick title acetylide is colorless oil.
TLC hexane Rf=0.43, UV+PMA
1H NMR（CDCl 3）
δ 0.08﹠amp; 0.12(2 singlet 6H)
0.90（s，9H）
0.99（m，1H）
1.09（d，3H）
1.19（m，1H）
1.46（m，2H）
1.74（m，3H）
2.12（d，1H）
2.30（m，1H）
2.41（m，1H）
2.71（m，1H）
4.37（m，1H）
5.38（d，1H）
5.55（m，1H）ppm.
E.(S)-4-(chlorine methoxyl group phosphinyl)-3-(((1, the 1-dimethyl ethyl) diphenylmethyl silylation) oxygen) butyric acid, methyl esters
Prepare phosphonyl chloride by following method by embodiment 25B dicyclohexyl amine salt partly.By at EtOAC and 5%KHSO 4Between distribute this dicyclohexyl amine salt (1.3 grams, 2.05 mmoles) and the regeneration free acid, organic layer 5%KHSO 4Anhydrous Na is used in (4 times) and salt water washing then 2SO 4Dry also vacuum-evaporation obtains free acid, is colourless viscosity oily matter.
This phosphonic acids mono-methyl (2.05 mmole) is dissolved in anhydrous CH 2Cl 2In (5 milliliters), use distillatory N, N-diethyl trimethyl silyl amine (515 microlitres, 4.1 mmoles) is handled, and this limpid colourless solution at room temperature stirred 1 hour in argon gas.Vacuum removal excess reagent and solvent, remaining oily matter is evicted wherein impurity from benzene (2 * 10 milliliters).
Will be in anhydrous CH 2Cl 2Thick silyl ester (～2.05 mmole) in (5 milliliters) and the dry DMF (1) is chilled to 0 ℃ (ice bath), and dropping distillatory oxalyl chloride (195 microlitres, 2.26 mmole) handle, then this yellow mixture stirred 15 minutes in argon gas under 0 ℃ and at room temperature stirred 45 minutes.This mixture of vacuum-evaporation is evicted wherein impurity from dry-out benzene (2 * 10 milliliters), obtains thick title phosphonyl chloride, is viscous yellow oil.
F. (1s-(1＜a(R *), 2＜a, 4a＜b, 8＜b, 8a＜a))-4-(((8-(((1, the 1-dimethyl ethyl) dimetylsilyl) oxygen)-1,2,4a, 5,6,7,8,8a-octahydro-2-methyl isophthalic acid-naphthyl) ethynyl) methoxyl group) phosphinyl)-3-(((1, the 1-dimethyl ethyl) butyric acid oxygen diphenylmethyl silylation)), methyl esters
Toward (356 milligrams of D acetylides partly, 1.17 mmole) in anhydrous THF(5 milliliter) in-78 ℃ solution in drip 1.6M n_BuLi hexane solution (730 microlitres, 1.17 mmole) handle, this limpid mixture stirred 30 minutes in argon gas under-78 ℃.Then with this acetylene negatively charged ion by overlap dropwise be transported to E part in effective 15 minutes phosphonyl chloride in anhydrous THF(6 milliliter) in-78 ℃ solution in.This yellow mixture stirred 30 minutes down at-78 ℃, then by dripping saturated NH 4The Cl(5 milliliter) stopped reaction, and it is heated to room temperature.This mixture is allocated in EtOAC and H 2Between the O, anhydrous Na is used in organic phase salt water washing 2SO 4Dry also vacuum-evaporation obtains 1.282 gram light yellow oil.This crude product by sudden strain of a muscle formula chromatography purification, is used (7: 3) hexane-EtOAC wash-out on silica gel.The evaporate fraction obtains 624 milligrams of (72.4%) title acetylene phosphinates, is flint glass shape thing.
TLC(7: 3) hexane-acetone, Rf=0.49, UV+PMA.
G. (1s-(1＜a(R *), 2＜a, 4a＜b, 8＜b, 8a＜a))-4-((2-(8-((1, the 1-dimethyl ethyl) dimetylsilyl) oxygen) decahydro-2-methyl isophthalic acid-naphthyl) ethyl) methoxyl group phosphinyl)-3-(((1, the 1-dimethyl ethyl) butyric acid oxygen diphenylmethyl silylation)), methyl esters
With the acetylene phosphinate (498 milligrams) of F part in CH 3The OH(6 milliliter) the 10%pt/c(200 milligram of the solution in) handle, and with this black suspension at H 2Jolting 48 hours on the Pa Er device (40Psi).By removing catalyzer with diatomite filtration, the new catalyzer of packing in this reaction mixture (150 milligrams) and at H 2Jolting 24 hours again on the Pa Er device (40Psi).By removing catalyzer with diatomite filtration, vacuum-evaporation filtrate obtains 448 milligrams of limpid glassy mass.This crude product carries out purifying with silica gel by dodging the formula chromatography, with (8: 2) hexane-EtOAC wash-out.Vacuum-evaporation product fraction obtains 334 milligrams of (66.5%) title compounds, is flint glass shape thing.
TLC(7: 3) EtOAC-hexane, Rf(3 kind diastereomer are a point)=0.42, the 4th diastereomer of Rf(is as a bit)=0.49, UV=PMA.
H (1s-(1＜a(R *), 2＜a, 4a＜b, 8＜b, 8a＜a))-4-((2-(decahydro-8-hydroxy-2-methyl-1-naphthyl) ethyl) methoxyl group phosphinyl)-3-(((1, the 1-dimethyl ethyl) diphenylmethyl silylation) oxygen) butyric acid, methyl esters
With the compound (248 milligrams, 0.334 mmole) of G part in CH 3Solution among the CN (4 milliliters) uses 48%HF in H 2Solution among the O (36 microlitres, 1 mmole) is handled, and this mixture at room temperature stirred 6.5 hours in argon gas.This mixture is allocated in EtOAC and saturated NaHco 3Between, anhydrous Na is used in organic layer salt water washing 2SO 4Dry also vacuum-evaporation obtains 227 milligrams of flint glass shape things.This crude product carries out purifying with silica gel by dodging the formula chromatography, with (4: 1) hexane-EtOAC wash-out, then with pure EtOAC wash-out.Vacuum-evaporation product fraction obtains 159 milligrams of (75.8%) pure title list alcohol, is colorless oil.
TLC(7: 3) acetone-hexane, Rf=0.5 UV(is weak)+PMA.
I. (1s-(1＜a(R *), 2＜a, 4a＜b, 8＜b, 8a＜a))-3-(((1, the 1-dimethyl ethyl) diphenylmethyl silylation) oxygen)-4-((2-(8-(2,2-dimethyl-1-oxo butoxy) butyric acid methoxyl group phosphinyl ethyl decahydro-2-methyl isophthalic acid-naphthyl))), methyl esters
With (147 milligrams of H alcohol partly, 0.234 mmole) solution in anhydrous pyridine (1.5 milliliters) is with 2,2-dimethyl-butyrylchlorine (160 microlitres, 1.17 mmole, 5 equivalents) handle, then handle with 4-dimethylaminopyridine (3 milligrams, 0.1 equivalent), this light yellow mixture heated 4 hours in 100 ℃ under argon gas.Cool off this mixture, be allocated between 1.0N Hcl and the EtOAC, organic layer 1.0N HCl(2 time) and the salt water washing, anhydrous Na used 2SO 4Dry also evaporation obtains 255 milligrams of light tan oily matter.This crude product carries out purifying with silica gel by dodging the formula chromatography, with (55: 45) hexane-EtOAc wash-out.Vacuum-evaporation product fraction obtains 112 milligrams of (65.9%) desired title dimethyl butyryl esters, is colorless oil.Hexane-acetone, Rf=0.62, UV+PMA.
J (1s-(1＜a(R *), 2＜a, 4a＜b, 8＜b, 8a＜a))-4-((2-(8-(2,2-dimethyl-1-oxo butoxy) decahydro-2-methyl isophthalic acid-naphthyl) ethyl) methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl esters
With the silyl ester (130 milligrams, 0.179 mmole) of I part in the THF(2 milliliter) in solution with Glacial acetic acid (HOAC) (41 microlitres, 0.0.716 mmole) and 1.1M(n-C 4H 9) 4The THF(490 microlitre of NF, 0.537 mmole) solution is handled continuously, and this mixture is stirred under argon gas spend the night.This mixture is allocated in EtoAC and 5%KHSO 4Between, use H 2O and salt water washing organic phase are used anhydrous Na 2SO 4Dry also vacuum-evaporation obtains 115 milligrams of colorless oil.This crude product carries out purifying with silica gel by dodging the formula chromatography, with (1: 1) hexane-acetone wash-out.Vacuum-evaporation product fraction obtains 72 milligrams (82.4%) desired title alcohol, is colorless oil.
TLC(1: 1) hexane-acetone, Rf=0.20, UV+PMA.
K. (1s-(1＜a(R *), 2＜a, 4a＜b, 8＜b, 8a＜a))-4-((2-(8-(2,2-dimethyl-1-oxo butoxy) decahydro-2-methyl isophthalic acid-naphthyl) ethyl) hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
The alcohol (72 milligrams, the 1.0N LiOH(0.52 milliliter of the solution in the 0.147 mmole) Yu diox (1.5 milliliters)) of J part is handled, and this mixture heated 1.5 hours in 55 ℃ (oil bath) under argon gas.Cool off this mixture, use H 2The O dilution is filtered also vacuum-evaporation to oily matter.This crude product carries out chromatography on HP-20 resin (3 centimetres of beds, the post of 15 mm dias), use H 2The O wash-out is then with (70: 30) H 2O-CH 3The oH wash-out.Vacuum-evaporation product fraction is dissolved in H 2The O(20 milliliter) also lyophilize obtains 55 milligrams (74%) desired title dilithium salt in, is white solid.
TLC（8∶1∶1）CH 2Cl 2-CH 2OH-CH 3COOH，Rf＝0.05，PMA。
Press C 23H 39O 7PLi 2+ 1.78 moles of H 2O(MW504.53) analyze,
Calculated value: C, 54.75; H, 8.50; P, 6.14
Measured value: C, 54.75; H, 8.64; P, 5.93
Embodiment 64
(S)-4-(((3 '-(4-fluorophenyl) spiral shell (pentamethylene-1,1 '-(1H) indenes-2-yl) ethynyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
A.3-(4-fluorophenyl)-the 1H-indenes
In argon gas under room temperature, in the solution (in 50 milliliters of ether, being prepared) of 4-fluorophenyl magnesium bromide by 6.43 milliliters of 4-bromofluorobenzenes and 1.71 gram Mg, dripped 2, the solution of 3-bihydrogen-1-indenone (6.61 grams, 50 mmoles) in anhydrous diethyl ether (20 milliliters) with 40 minutes.After at room temperature stirring 1 hour, by dripping saturated NH 4Cl solution (15 milliliters) stops this reaction.This mixture Et 2The O dilution, with saturated NaCl solution washing, dry (MgSO 4) and evaporation.
This resistates is dissolved in the Glacial acetic acid (15 milliliters), and under argon gas, refluxed 30 minutes.Steam acetic acid and evict the impurity secondary from methyl.This resistates (9.45 gram) carries out purifying with silica gel by dodging the formula chromatography, uses the hexane wash-out, obtains title compound (8.174 grams, 78%), is colorless oil, it is left standstill post crystallization, m.p.38～40 ℃ TLC(hexane) Rf=0.21.
B.3 '-(4-fluorophenyl) spiral shell (pentamethylene-1,1 '-(1H) indenes)
In argon gas under 0 ℃, to the compound (10.676 grams, 50.8 mmoles) of A part in anhydrous THF(90 milliliter) in solution in, add solid potassium tert-butoxide (12.2 grams, 109 mmoles) in batches.After stirring 30 minutes under 0 ℃, drip 1,4-dibromobutane (6.50 milliliters, 101 mmoles).The gained mixture is heated to room temperature, stirred 2 hours, be allocated in EtOAC-5%KHSO then 4Between (each 150 milliliters).Organic phase is with saturated NaCl solution washing, dry (Na 2SO 4) and be evaporated to dried.This crude product carries out purifying with silica gel by dodging the formula chromatography, uses the hexane wash-out, obtains title compound (9.43 grams, 70%), is colorless oil.TLC(Et 2The O-hexane; 1: 9) Rf=0.63 of Rf=0.69(A part of compounds).
C.3 '-(4-fluorophenyl) spiral shell (pentamethylene-1,1 '-(1H) indenes)-2 '-formaldehyde
In argon gas under 0 ℃, to the compound (9.30 grams, 35.2 mmoles) of B part in anhydrous CH 2Cl 2150 milliliters) in solution in, add 1.0M TiCl 4In CH 2Cl 2Solution in (70 milliliters, 70 mmoles).Drip 1 to gained sap green solution, 1-dichloromethyl methyl ether (3.50 milliliters, 38.7 mmoles) is handled.After 0 ℃ stirring was also at room temperature stirred 1 hour in 1 hour down, this mixture was poured on the cold full NaHCo of closing 3On the solution.Separate organic phase, dry (Na 2SO 4) and be evaporated to dried.This crude product carries out purifying with silica gel by dodging the formula chromatography, uses Et 2O-hexane (5: 95) wash-out obtains title compound (8.233 grams, 80%), is yellow oil.This oily matter carries out crystallization with hexane, obtains pure title compound (6.778 grams, 66%), is light yellow crystallization, 116～117 ℃.TLC(Et 2The O-hexane; 15.85) Rf=0.56.
Press C 20H 17OF analyzes, calculated value: C, 82.17; H, 5.86; F, 6.50
Measured value: C, 83.13; H, 5.82; F, 6.29
D.2 '-ethynyl-3 '-(4-fluorophenyl) spiral shell (pentamethylene-1,1 '-(1H) indenes
In argon gas under-78 ℃, to potassium tert.-butoxide (0.672 gram, 6.00 mmole) in anhydrous THF(8 milliliter) in solution in, drip dizaomethyl dimethyl phosphonate (0.960 gram, 6.40 mmole, press J.Org.chem.36,1379(1971) in method be prepared) in anhydrous THF(4 milliliter) and in solution.-78 ℃ down stir 5 minutes after, with the compound that dripped the C part in 10 minutes (1.168 restrain 4.00 mmoles) in the THF(8 milliliter) in solution.-78 ℃ of stirrings 3 hours down, after-45 ℃ stirring was also at room temperature stirred 1 hour in 1.5 hours down, this mixture dilutes with hexane (50 milliliters), and uses 5%KHSO 4Solution washing.Organic phase is with saturated NaCl solution washing, dry (Na 2So 4) and be concentrated into small volume (not dried).This yellow solution dodges the formula chromatography with silica gel, uses the hexane wash-out.Merge the fraction that contains product, handle with butylated hydroxytoluene (BHT) (0.080 gram, 0.36 mmole), and be concentrated into small volume (5～10 milliliters), it is directly used in the next step with the solution form.TLC(Et 2The O-hexane; 1: 9) R angle=0.57. 1H NMR(270MHz, CDCl 3), adopt BHT be interior mark (1.45ppm, 18H, S), show have the desired acetylide of 3.10 mmoles (productive rate 77.5%) (3.32ppm, 1H, S).
E.(S)-4-(chlorine methoxyl group phosphinyl)-3-(((1, the 1-dimethyl ethyl) diphenylmethyl silylation) oxygen) butyric acid, methyl esters
Described in embodiment 29J part, adopt following dosage, trimethyl silyl diethylamide (1.36 milliliters, 10.85 mmoles), CH 2Cl 2(15 milliliters); Oxalyl chloride (0.50 milliliter, 5.73 mmoles), DMF(1 drips), CH 2Cl 2(15 milliliters) are by dicyclohexyl amine salt (3.44 grams, 54.4 mmoles) the preparation title phosphonyl chloride of embodiment 25B part.
F.(S)-3-(((1, the 1-dimethyl ethyl) diphenylmethyl silylation) oxygen)-4-(((3 '-(4-fluorophenyl) spiral shell (pentamethylene-1,1 '-(1H) indenes)-the 2-yl) ethynyl) the methoxyl group phosphinyl) butyric acid, methyl esters
With the hexane solution of the acetylide (3.10 mmoles+0.36 mmole BHT) of D part with anhydrous THF(15 milliliter) dilute and under argon gas, be chilled to-78 ℃.Dripping 1.6M n-BuLi hexane solution (2.16 milliliters, 3.46 mmoles) by syringe in this solution then handles.-78 ℃ down stir 45 minutes after, this anion solutions is transferred to the phosphonyl chloride (54.4 mmole) of E part in anhydrous THF(15 milliliter by sleeve pipe) in-78 ℃ of solution in.After stirring 1 hour under-78 ℃, by dripping saturated NH 4The Cl(15 milliliter) stops this reaction, and it is heated to room temperature.This mixture extracts with EtOAC, this extraction liquid 5%KHSO 4, saturated NaHCO 3With saturated NaCl solution washing, dry (Na 2SO 4) and be evaporated to driedly, this crude product carries out purifying with silica gel by dodging the formula chromatography, with EtOAC-hexane (25: 75) wash-out, obtains title compound (1.781 grams calculate according to the compound of D part, and productive rate is 80%), is light yellow glassy mass.
TLC(acetone-hexane; 1: 1) Rf=0.46
G.(S)-4-(((3 '-(4-fluorophenyl) spiral shell (pentamethylene-1,1 '-(1H) indenes)-the 2-yl) ethynyl) the methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl esters
In argon gas under room temperature, to the compound (1.00 grams, 1.39 mmoles) of F part in anhydrous THF(5 milliliter) in solution in, add Glacial acetic acid (0.32 milliliter, 5.59 mmoles) and 1.1M(n-C 4H 9) 4The solution (3.80 milliliter, 4.18 mmoles) of NF in THF.After at room temperature stirring 18 hours, this mixture EtOAC(50 milliliter) dilution, usefulness 1N HCl(3 * 30 milliliters) and saturated NaCl solution continuous washing, dry (Na 2SO 4) and be evaporated to dried.This resistates is dissolved in Et 2The O(20 milliliter) in, cooling and with the processing of excessive ether diazomethane in ice bath.After the ether evaporation, the resistates of gained carries out purifying with silica gel by dodging the formula chromatography, with acetone-hexane (3: 7) wash-out, obtains title compound (0.595 gram, 89%), is flint glass shape thing.
TLC(acetone-hexane; 1: 1) Rf=0.29.
H.(S)-4-(((3 '-(4-fluorophenyl) spiral shell (pentamethylene-1,1 '-(1H) indenes)-the 2-yl) ethynyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt
Under room temperature, (0.580 gram in the solution in the 1.20 mmole) Yu dioxs (6 milliliters), adds 1N LiOH solution (4.2 milliliters, 4.2 mmoles) to G compound partly in argon gas.After at room temperature stirring 3 hours, this mixture is collected white depositions with acetonitrile (20 milliliters) dilution, with acetonitrile washing and vacuum-drying, obtains thick title product (0.670 gram), is white solid.Be suspended in this crude product in the water (10 milliliters) and be added to short HP-20(15 milliliter bed volume, 1 inch diameter) on the chromatographic column, water (300 milliliters) wash-out is then used the MeOH(300 milliliter) wash-out.Merge and contain the fraction of product and be evaporated to dried.This solid residue is developed with acetonitrile, obtains pure title product (0.550 gram, 98%), is white solid, mp301～303 ℃ (decomposition).
TLC(i-C 3H 7The dense NH of oH- 4OH-H 2O; 7: 2: 1) Rf=0.48.
Embodiment 65～122
Method according to described in noted earlier and the foregoing description can prepare following additional compounds.
Figure 881036994_IMG209
Figure 881036994_IMG212
Figure 881036994_IMG213
Figure 881036994_IMG215
Figure 881036994_IMG217
Figure 881036994_IMG218
Figure 881036994_IMG219
Figure 881036994_IMG220
Figure 881036994_IMG222
Figure 881036994_IMG223

Claims (8)

1, a kind of preparation has the method for the compound of following formula,
Figure 881036994_IMG2
Wherein R is OH or lower alkoxy;
X is CH 2, CH 2CH 2-,-CH 2CH 2CH 2-,-CH=CH-,-C ≡ C-or-CH 2O-(wherein O links to each other with Z);
Z is a hydrophobic conjugated group,
R xBe hydrogen or low alkyl group, the form that this compound can free acid exists, or exists with the form of hydrolyzable on the physiology and acceptable ester, or exists with the form of salt,
(A) X wherein be-CH=CH for the moment, this method comprises, makes the acetylene phosphinate with following formula carry out the silyl ether cracking,
Figure 881036994_IMG3
Formation has the diester of following formula,
If desired, this diester is changed into monoesters with following formula,
Figure 881036994_IMG5
Have following formula subsalt,
Figure 881036994_IMG6
Have following formula secondary salt,
Figure 881036994_IMG7
Or has a diacid of following formula;
Figure 881036994_IMG8
(B) X wherein be-during CH=CH-(suitable), this method comprises, makes the acetylene phospho acid fat reduction with following formula,
Figure 881036994_IMG9
Formation has the silyl ether of following formula,
Figure 881036994_IMG10
Make this silyl ether carry out the silyl ether cracking, form diester with following formula,
Figure 881036994_IMG11
If desired, this diester is transformed into monoesters with following formula,
Have following formula subsalt,
Figure 881036994_IMG13
Have following formula acid,
Figure 881036994_IMG14
Or has a secondary salt of following formula;
(C) X wherein is-CH 2-CH 2In-time, this method comprises, makes the silyl ether reduction with following formula,
Figure 881036994_IMG16
Formation has the silyl ether of following formula,
Figure 881036994_IMG17
Make this silyl ether carry out the silyl ether cracking, form diester with following formula,
Figure 881036994_IMG18
If desired, this diester is transformed into subsalt with following formula,
Have following formula acid,
Have following formula secondary salt,
Or has a diacid of following formula;
(D) X wherein be-during CH=CH-(instead), this method comprises, makes the silyl ether with following formula carry out the silyl ether cracking,
Figure 881036994_IMG23
Formation has the hydroxyl diester of following formula,
If desired, this hydroxyl diester is transformed into subsalt with following formula,
Figure 881036994_IMG25
Have following formula acid,
Figure 881036994_IMG26
Have following formula secondary salt,
Figure 881036994_IMG27
Or has the diacid of following formula accordingly;
Figure 881036994_IMG28
(E) X wherein be-during CH=CH-(instead), this method comprises, makes the phosphonyl chloride with following formula
With the condensation of Acetacetic acid alkyl ester dianion, form one phosphonic acids ester with following formula,
Make this one phosphonic acids ester reduction, form phospho acid diester with following formula,
If desired, this diester is transformed into subsalt with following formula,
Have following formula acid,
Figure 881036994_IMG33
Have following formula secondary salt,
Or has a diacid of following formula;
(F) X wherein is-CH 2-,-CH 2CH 2-or-CH 2CH 2CH 2In-time, this method comprises, makes phosphonyl chloride (wherein a is 1,2 or 3) and the condensation of Acetacetic acid alkyl ester dianion with following formula,
Figure 881036994_IMG36
Formation has the one phosphonic acids ester of following formula,
Figure 881036994_IMG37
Make this one phosphonic acids ester reduction, form diester with following formula,
Figure 881036994_IMG38
If desired, this diester is changed into subsalt with following formula,
Have following formula acid,
Have following formula secondary salt,
Figure 881036994_IMG41
Or has a diacid of following formula;
(G) X wherein is-(CH 2O)-time, this method comprises, makes phosphonyl chloride and the condensation of Acetacetic acid alkyl ester dianion with following formula,
Formation has the one phosphonic acids ester of following formula,
Figure 881036994_IMG44
Make this one phosphonic acids ester reduction, form phospho acid diester with following formula,
Figure 881036994_IMG45
If desired, this diester is changed into subsalt with following formula,
Figure 881036994_IMG46
Have following formula acid,
Have following formula secondary salt,
Figure 881036994_IMG48
Or has a diacid of following formula.
2, the method for claim 1, hydrophobic conjugated group wherein is a lipophilic group, when it links to each other with the top side chain that is similar to HMG of molecule by suitable linking group (X), can combine with the hydrophobic capsule that is not used for bound substrates HMG CoA of enzyme molecule, its drug effect is strengthened with respect to the compound of Z=H.
3, the method for claim 1, wherein Z is
Figure 881036994_IMG51
R wherein 1, R 2, R 2aAnd R 2bIdentical or different, all be selected from the phenyl or the ORy of H, halogen, low alkyl group, haloalkyl, phenyl, replacement respectively, wherein Ry is the phenyl-low alkyl group of H, alkanoyl, benzoyl, phenyl, halogenophenyl, phenyl-low alkyl group, low alkyl group, cinnamyl, haloalkyl, allyl group, cycloalkyl-low alkyl group, adamantyl-low alkyl group or replacement;
When Z is following group,
Figure 881036994_IMG52
R 5And R 5 'Identical or different, be H, low alkyl group or OH;
R 6Be low alkyl group , for example , or aryl CH 2-;
R 6aBe low alkyl group, hydroxyl, oxo or halogen; Q is 0,1,2 or 3;
R 7Be H or low alkyl group;
When Z is following group,
Figure 881036994_IMG55
R 3And R 4There is one to be
Figure 881036994_IMG57
, another is low alkyl group, cycloalkyl or phenyl-(CH 2) p-, p is 0,1,2,3 or 4;
R wherein 13Be hydrogen, low alkyl group, lower alkoxy (except the tert.-butoxy), halogen, phenoxy group or benzyloxy;
R 14Be hydrogen, low alkyl group, lower alkoxy, halogen, phenoxy group or benzyloxy;
R 14aBe hydrogen, low alkyl group, lower alkoxy or halogen;
Supplementary condition are to work as R 13During for hydrogen, R 14And R 14aAll be necessary for hydrogen, work as R 14During for hydrogen, R 14aBe necessary for hydrogen, R 13And R 14In have one at the most for trifluoromethyl, R 13And R 14In have one at the most for phenoxy group, R 13And R 14In have one at the most for benzyloxy;
R 8Be hydrogen, C 1-4Alkyl, C 3-6Cycloalkyl, C 1-4Alkoxyl group (except the tert.-butoxy), trifluoromethyl, fluorine, chlorine, phenoxy group or benzyloxy;
R 9Be hydrogen, C 1-3Alkyl, C 1-3Alkoxyl group, trifluoromethyl, fluorine, chlorine, phenoxy group or benzyloxy, supplementary condition are to work as R 8During for hydrogen, R 9Must be along being hydrogen, R 8And R 9In have one at the most for trifluoromethyl, R 8And R 9In have one at the most for phenoxy group, R 8And R 9In have one at the most for benzyloxy;
R 10And R 11Be selected from respectively hydrogen, alkyl, cycloalkyl, adamantyl-1 or
Figure 881036994_IMG58
R wherein 13, R 14And R 14aLimit q=0,1,2,3 or 4 as the front;
Y is O, S or N-R 10;
When Z is following group,
Figure 881036994_IMG59
R aBe H or uncle or secondary 1-6C alkyl;
R bBe uncle or secondary 1-6C alkyl;
Perhaps R a+ R bBe (CH 2) r or (suitable)-CH 2-CH=CH-CH 2;
R=2,3,4,5 or 6;
R 12For low alkyl group, cycloalkyl or
R wherein 8, R 9, R 13, R 14And R 14aAs above limit;
When Z is following group,
Figure 881036994_IMG61
R 15And R 16All be H, Cl, Br, CN, CF 3, phenyl, 1-4C alkyl, 2-8C alkoxy carbonyl ,-CH 2OR 17Or-CH 2OCONHR 18;
R 17Be H or 1-6C alkanoyl;
R 18For alkyl or by any phenyl that replaces of F, Cl, Br or 1-4C alkyl;
Perhaps, R 15And R 16Be together-(CH 2) s-,-CH 2OCH 2-,-CON(R 19) CO-or-CON(R 20) N(R 21) CO-;
S=3 or 4;
R 19=H, 1-6C alkyl, phenyl or benzyl;
R 20And R 21Be H, 1-4C alkyl or benzyl; X is-CH 2-,-CH 2CH 2-or-CH 2CH 2CH 2-;
When Z is following group,
Figure 881036994_IMG62
R 22For low alkyl group, cycloalkyl, adamantyl-1 or
Figure 881036994_IMG63
T=1,2,3 or 4;
R 23And R 23aIdentical or different, all be selected from hydrogen, low alkyl group, lower alkoxy (except the tert.-butoxy), halogen, phenoxy group or benzyloxy respectively;
Supplementary condition are to work as R 23During for hydrogen, R 23aBe necessary for hydrogen, R 23And R 23aIn have one at the most for trifluoromethyl, R 23And R 23aIn have one at the most for phenoxy group, R 23And R 23aIn have one at the most for benzyloxy;
When X is-CH 2During O-(carbon is connected on the P, and O is connected on the Z), hydrophobic conjugated group Z will for
Figure 881036994_IMG64
4, method as claimed in claim 3, wherein X be-CH=CH-or-C ≡ C-, R is OH or alkoxyl group, Z is
5, the method for claim 1, wherein formed compound has following title:
(S)-4-(((E)-2-(4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl 2-yl) vinyl) the hydroxyl oxygen phosphino-)-3-hydroxybutyric acid or its dilithium salt;
(S)-4-((2-(4 '-fluoro-3,3 ', the 5-trimethylammonium-(1,1 '-biphenyl)-the 2-yl) ethyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, its methyl ester or one or two an alkali metal salts;
(S)-4-(((4 '-fluoro-3,3 ', the 5-trimethylammonium-(1,1 '-biphenyl)-the 2-yl) ethynyl) the methoxyl group phosphinyl)-3-hydroxybutyric acid or its methyl ester;
(5Z)-4-((2-(4 '-fluoro-3,3 ', the 5-trimethylammonium-(1,1 '-biphenyl)-the 2-yl) vinyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, its methyl ester;
(S)-and 4-((2-(3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indoles-2-yl) ethyl) the methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl ester;
(S)-4-((2-((1,1 '-biphenyl)-the 2-yl) ethyl)-methoxyl group phosphinyl-3-hydroxybutyric acid, methyl ester;
(S)-4-((2-(4 '-fluoro-3,3 ', the 5-trimethylammonium-(1,1 '-biphenyl)-the 2-yl) ethyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt;
(S)-4-((2-(4 '-fluoro-3,3 ', the 5-trimethylammonium-(1,1 '-biphenyl)-the 2-yl) ethynyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt;
(5Z)-4-((2-(4 '-fluoro-3,3 ' 5-trimethylammonium-(1,1 '-biphenyl)-the 2-yl) vinyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt;
(S)-and 4-((2-(3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indoles-2-yl) ethyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt;
(S)-4-((2-((1,1 '-biphenyl)-the 2-yl) ethyl)-the hydroxyl oxygen phosphino-)-the 3-butyric acid, dilithium salt;
(S)-4-(hydroxyl methoxyl group phosphinyl)-3-(((1, the 1-dimethyl ethyl) diphenylmethyl silylation) oxygen base) butyric acid, methyl ester, or its dicyclohexyl amine (1: 1) salt;
(S)-and 4-((2-(1-(4-fluorophenyl)-3-(1-methylethyl)-1-indoles-2-yl) ethynyl) the hydroxyl oxygen phosphino-)-3-hydroxybutyric acid or its dilithium salt or its methyl ester;
(S)-and 4-((2-(1-(4-fluorophenyl)-3-(1-methylethyl)-1H-indoles-2-yl) ethyl) the hydroxyl oxygen phosphino-)-3-hydroxybutyric acid or its dilithium salt or its methyl ester;
(E)-and 4-((2-(3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indoles-2-yl) vinyl) the hydroxyl oxygen phosphino-)-3-hydroxybutyric acid or its dilithium salt or its methyl ester;
4-((2-(4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)-the 2-yl) ethyl) the hydroxyl oxygen phosphino-)-3-hydroxybutyric acid or its dilithium salt or its methyl ester;
(E)-4-((2-(4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)-the 2-yl) vinyl) the hydroxyl oxygen phosphino-)-3-hydroxybutyric acid or its dilithium salt or its methyl ester;
(S)-4-(((2,4-dimethyl-6-((4-fluorophenyl)-methoxyl group) phenyl) ethyl) hydroxyl oxygen phosphino-)-3-hydroxybutyric acid or its dilithium salt or its methyl ester;
(S)-4-(((2,4-dimethyl-6-((4-fluorophenyl)-methoxyl group) phenyl) ethynyl) hydroxyl oxygen phosphino-)-3-hydroxybutyric acid or its dilithium salt or its methyl ester;
(S)-4-((2-(3, the 5-dimethyl (1,1 '-biphenyl)-the 2-yl) ethyl) the hydroxyl oxygen phosphino-)-3-hydroxybutyric acid or its dilithium salt or its methyl ester;
(S)-4-((2-(4 '-fluoro-3, the 5-dimethyl (1,1 '-biphenyl)-the 2-yl) ethyl) the hydroxyl oxygen phosphino-)-3-hydroxybutyric acid or its dilithium salt or its methyl ester;
(S)-4-((2-((1,1 '-biphenyl)-the 2-yl) ethynyl)-the hydroxyl oxygen phosphino-)-3-hydroxybutyric acid or its dilithium salt or its methyl ester;
(S)-and 4-((2-(5-(4-fluorophenyl)-3-(1-methylethyl)-1-phenyl-1H-pyrazoles-4-yl) ethynyl) the methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl ester;
(S)-and 4-((2-(5-(4-methyl fluoride)-3-(1-methylethyl)-1-phenyl-1H-pyrazoles-4-yl) ethynyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt;
(E)-and 4-((2-(5-(4-fluorophenyl)-3-(1-methylethyl)-1-phenyl-1H-pyrazoles-4-yl) vinyl) the methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl ester;
(E)-and 4-((2-(5-(4-fluorophenyl)-3-(1-methylethyl)-1-phenyl-1H-pyrazoles-4-yl) vinyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt;
(S)-and 4-((2-(5-(4-fluorophenyl)-3-(1-methylethyl)-1-phenyl-1H-pyrazoles-4-yl) ethyl) the methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl ester;
(S)-and 4-((2-(5-(4-fluorophenyl)-3-(1-methylethyl)-1-phenyl-1H-pyrazoles-4-yl) ethyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt;
(S)-and 4-((2-(3-(4-fluorophenyl)-5-(1-methylethyl)-1-phenyl-1H-pyrazoles-4-yl) ethyl) the methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl ester;
(S)-and 4-((2-(3-(4-fluorophenyl)-5-(1-methylethyl)-1-phenyl-1H-pyrazoles-4-yl) ethyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt;
(S)-and 4-((2-(3-(4-fluorophenyl)-5-(1-methylethyl)-1-phenyl-1H-pyrazoles-4-yl) ethynyl) the methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl ester;
(S)-and 4-((2-(3-(4-fluorophenyl)-5-(1-methylethyl)-1-phenyl-1H-pyrazoles-4-yl) ethynyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt;
(S)-and 4-(((4-(4-fluorophenyl)-1-(1-methylethyl)-3 phenyl-1H-pyrazoles-5-yl) ethynyl) the methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl ester;
(S)-and 4-(((4-(4-fluorophenyl)-1-(1-methylethyl)-3-phenyl-1H-pyrazoles-5-yl) ethynyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt;
(S)-and 4-((2-(4-(4-fluorophenyl)-1-(1-methylethyl)-3-phenyl-1H-pyrazoles-5-yl) ethyl) the methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl ester;
(S)-and 4-((2-(4-(4-fluorophenyl)-1-(1-methylethyl)-3-phenyl-1H-pyrazoles-5-yl) ethyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt;
(S)-and 4-(((1-(4-fluorophenyl)-4-(1-methylethyl)-2-phenyl-1H-imidazoles-5-yl) ethynyl) the methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl ester;
(S)-and 4-(((1-(4-fluorophenyl)-4-(1-methylethyl)-2-phenyl-1H-imidazoles-5-yl) ethynyl) the methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl ester;
(S)-and 4-((2-(1-(4-fluorophenyl)-4-(1-methylethyl)-2-phenyl-1H-imidazoles-5-yl) ethyl) the methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl ester;
(S)-and 4-((2-(1-(4-fluorophenyl)-4-(1-methylethyl)-2-phenyl-1H-imidazoles-5-yl) ethyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt;
(S)-4-(((2-(cyclohexyl methyl)-4,6-3,5-dimethylphenyl) ethynyl) hydroxyl oxygen phosphino-)-3-hydroxybutyric acid or its dilithium salt or its methyl ester;
4-((2-(2-(cyclohexyl methyl)-4,6-3,5-dimethylphenyl) vinyl) hydroxyl oxygen phosphino-)-3-hydroxybutyric acid or its dilithium salt or its methyl ester;
(S)-4-((2-(2-(cyclohexyl methyl)-4,6-3,5-dimethylphenyl) ethyl) hydroxyl oxygen phosphino-)-3-hydroxybutyric acid or its dilithium salt or its methyl ester;
4-((((4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)-the 2-yl) the oxygen base) methyl) the hydroxyl oxygen phosphino-)-3-hydroxybutyric acid or its dilithium salt or its methyl ester;
4-(((4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)-the 2-yl) methyl) the hydroxyl oxygen phosphino-)-3-hydroxybutyric acid or its dilithium salt or its methyl ester;
(S)-4-(((1-(4-fluorophenyl)-3-methyl-2-naphthyl) ethynyl) hydroxyl oxygen phosphino-)-3-hydroxybutyric acid or its dilithium salt or its methyl ester;
(E)-4-((2-(1-(4-fluorophenyl)-3-methyl-2-naphthyl) vinyl) hydroxyl oxygen phosphino-)-3-hydroxybutyric acid or its dilithium salt or its methyl ester;
(S)-4-((2-(1-(4-fluorophenyl)-3-methyl-2-naphthyl) ethyl) hydroxyl oxygen phosphino-)-3-hydroxybutyric acid or its dilithium salt or its methyl ester;
4-((3-(4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)-the 2-yl) propyl group) the methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl ester;
4-((3-(4 '-fluoro-3,3 ', the 5-trimethylammonium (1,1 '-biphenyl)-the 2-yl) propyl group) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt;
(1S-(1＜a(R *), 2＜a, 4a＜b, 8＜b, 8a＜a))-4-((2-(8-(2,2-dimethyl-1-oxo butoxy) decahydro-2-methyl isophthalic acid-naphthyl) ethyl) methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl ester;
(1S-(1＜a(R *), 2＜a, 4a＜b, 8＜b, 8a＜a))-4-((2-(8-(2,2-dimethyl-1-oxo butoxy) decahydro-2-methyl isophthalic acid-naphthyl) ethyl) hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt;
(S)-4-((3 '-(4-fluorophenyl) spiral shell) pentamethylene-1,1 '-(1H) indenes)-the 2-yl) ethynyl) the methoxyl group phosphinyl)-the 3-hydroxybutyric acid, methyl ester; Or
(S)-4-(((3 '-(4-fluorophenyl) spiral shell) pentamethylene-1,1 '-(1H) indenes)-the 2-yl) ethynyl) the hydroxyl oxygen phosphino-)-the 3-hydroxybutyric acid, dilithium salt.
6, a kind of intermediate with following structure,
Comprise its all steric isomers, wherein R 1 aBe alkoxyl group or hydroxyl; R 1 bFor hydroxyl, Cl ,-C ≡ C-Z ,-CH 2-Z ,-CH 2CH 2CH 2-Z ,-CH 2O-Z ,-CH=CH-Z or-CH 2CH 2-Z, wherein Z is a hydrophobic conjugated group, condition is to work as R 1 bDuring for hydroxyl, R 1 aBe hydroxyl or alkoxyl group; Or a kind of intermediate with following structure,
Comprise its all steric isomers, wherein X is (CH 2) a ,-CH=CH-,-C ≡ C-or-CH 2O, a are 1,2 or 3, and Z is a hydrophobic conjugated group.
7, a kind of method for preparing the intermediate of claim 6, wherein R 1 aBe O alkyl, R 1 bFor-CH=CH-Z, this method comprises, in the presence of a kind of inert organic solvents, replaces the agent treated vinyl iodide with a kind of metal,
Figure 881036994_IMG68
In the presence of a kind of inert organic solvents, the gained negatively charged ion and the cooling solution of the phosphonyl chloride with following structure are reacted then
Figure 881036994_IMG69
8, a kind ofly prepare the method with intermediate of following structure as claimed in claim 6,
This method comprises that in the presence of a kind of inert organic solvents, apparatus has the dianion of following structure
Processing has the cooling solution of the phosphonyl chloride of following structure.
Figure 881036994_IMG72
CN88103699A 1987-05-22 1988-05-21 Phosphorated 3-hydroxyl-3-first glutaryl CoA-reductase inhibitors, new intermediate and method Pending CN1030761A (en)

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