CN85106878A - The method for preparing compound - Google Patents

The method for preparing compound Download PDF

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CN85106878A
CN85106878A CN 85106878 CN85106878A CN85106878A CN 85106878 A CN85106878 A CN 85106878A CN 85106878 CN85106878 CN 85106878 CN 85106878 A CN85106878 A CN 85106878A CN 85106878 A CN85106878 A CN 85106878A
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compound
methyl
structural formula
group
alkyl
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安德鲁·约翰·吉尔比·巴克斯特
肯尼思·约翰·吉尔德
约翰·狄克逊
艾伦·查尔斯·廷克
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Fisons Ltd
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Fisons Ltd
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Priority claimed from GB848426563A external-priority patent/GB8426563D0/en
Priority claimed from GB848426562A external-priority patent/GB8426562D0/en
Priority claimed from GB848426570A external-priority patent/GB8426570D0/en
Priority claimed from GB848426569A external-priority patent/GB8426569D0/en
Priority claimed from GB848426571A external-priority patent/GB8426571D0/en
Priority claimed from GB848426559A external-priority patent/GB8426559D0/en
Priority claimed from GB848426560A external-priority patent/GB8426560D0/en
Priority claimed from GB848430296A external-priority patent/GB8430296D0/en
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Abstract

The present invention relates to the preparation method of compound shown in the drawings, and the application aspect the treatment cardiovascular disorder.R among the figure 1, R 2, R 3, R 4, R 5And R 6Definition such as specification sheets described in.

Description

The method for preparing compound
The invention relates to new compound, prepare the method and the intermediate of these compounds and the prescription that contains these compounds.
According to the present invention, can obtain the compound of structure such as structural formula I,
Figure 85106878_IMG7
R wherein 1Be hydrogen atom or C 1～C 6Alkyl,
R 3And R 5Be-(CH 2) x-(CHR 34) yR 35, they can be identical or different,
X is from 0 to 7 integer, comprises 0 and 7,
Y is 0 or 1,
R 34Be hydrogen atom, C 1～C 6Alkyl or the following cycloalkyl of eight carbon atoms (containing eight carbon atoms),
R 35It can be hydrogen atom; Be to have substituent C 1～C 6Alkyl, substituting group can be: H, halogen atom, C 1～C 6Alkoxyl group or hydroxyl, whether replace that to reach the position of substitution be selectable; Be to contain O, N or S(O) nQuaternary, five yuan or hexa-member heterocycle, on the heterocycle C can be arranged 1～C 6Alkyl replace, whether replace and reach the position of substitution and can select; Be following cycloalkyl or cycloalkenyl groups of eight carbon atoms (containing eight carbon atoms), wherein cycloalkyl itself can form bridged bond again or by C 1～C 6Alkyl replace, form bridged bond or whether replace and the position can be selected, also can and on phenyl ring; Be group-CH=CHR B, R wherein BBe the following cycloalkyl of eight carbon atoms (containing eight carbon atoms); Or C 1～C 6Alkylamino, wherein alkyl can be replaced by phenyl ring, whether replaces to reach the position and can select; When X is from 1 to 7 integer when (comprising 1 and 7), R 35Can be cyano group ,-OSO 2R 33Or the group of structure such as structural formula II or III,
Figure 85106878_IMG8
R wherein 11And R 12Be C 1～C 6Alkyl or phenyl, they can be identical or different,
R 33Be C 1～C 6Alkyl or C 1～C 6Alkyl phenyl,
R 2And R 6Can be identical or different, they can be CN, CHO or C 1～C 6Alkyl, can insert on these alkyl Sauerstoffatom and by halogen atom, H ,-COOH or its C 1～C 6Alkyl ester, C 1～C 6'beta '-ketoester group, alpha-amino group-6-hydroxy pyrimidine-4-base or-NR 14R 15Group replaces, inserts and whether replaces to reach the position and can select,
R 14And R 15Can be identical or different, they can be H, C 1～C 6Alkyl ,-C(-NCN) S alkyl (C 1～C 6) or the group of structure such as structural formula IV, also can form segment together,
Figure 85106878_IMG9
-CR 6=N-CR 17=CR 13-,-CH 2CH 2N(R 19) CH 2CH 2-or-CO(phosphorus-benzene methylene base) CO-,
R 16, R 17And R 18Be C 1～C 6Alkyl, they can be identical or different,
R 19It can be hydrogen atom; Be C 1～C 6Alkyl, can be replaced by phenyl on the alkyl, whether replace that to reach the position be selectable, can be replaced by halogen atom on the phenyl, whether replace and reach the position and can select; Be-CONR 20R 21; Or contain N or contain N and the unsaturated five-ring of S,
R 20And R 21Can be hydrogen atom or C 1～C 6Alkyl, they can be identical or different;
R 4Can be to have three or four substituent phenyl, or contain the unsaturated quinary heterocyclic radical of one of O, S, N; R 4Can have following substituting group: CF 3, XR 22, NO 2, halogen atom, CN, C 1～C 6Alkyl, formyl radical, oxalic acid ester group,--N(R 23) COR 24,-CONR 25R 26, or amino, can be substituted with benzenesulfonyl or trifluoroacetyl group on amino; R 4Go up and be connected R 4Have a substituting group on the atom adjacent with the atom of molecule other parts,
R 22Be phenyl or C 1～C 6Alkyl, can be substituted with halogen atom on the alkyl, whether replace and reach the position and can select,
X is O or S(O) n,
N is 0,1 or 2,
R 23, R 24, R 25Or R 26Can be hydrogen atom or C 1～C 6Alkyl, they can be identical or different,
If ⅰ) work as R 1Be hydrogen atom or methyl, R 2Be CH 2F, R 3Be CH 2, R 5When being sec.-propyl or cyclopentyl, R then 4Not 2-trifluoromethyl-3-chloro-6-fluorophenyl,
ⅱ) work as R 1Be hydrogen atom, R 2Be CH 2F, R 3Be methyl, R 5When being the 1-methylethyl, R then 4Not 2,3-two chloro-6-fluorophenyls.
ⅲ) work as R 4When being heterocyclic radical, R then 2And R 6Have at least one not to be alkyl or alkoxyl group-alkyl.
Or contain the structural formula I compound of basic nitrogen atom and the addition piece of the acid of can being used as medicine.
According to the present invention, we can further provide preparation structural formula I compound and with the acid of can being used as medicine add caked method, this method comprises:
A) reaction of the compound of structure such as structural formula V, VII, X and XI V,
R 4CHO Ⅴ
R 5OOCCH 2COR 6Ⅶ
R 3OOCCH 3COR 2Ⅹ
R 1NH 2ⅪⅤ
Or their partial condensate.
R wherein 1, R 2, R 3, R 4, R 5And R 6Structure such as front define.
B) respective compound of structural formula I compound (is wherein contained group-S(O) m-, m=0,1) carry out selective oxidation reaction, preparation contains group-S(O) mThe structural formula I compound of-(m=1,2).
C) by the respective compound of structural formula I compound and the reaction (R in the respective compound of fluorizating agent 6And R 2One of be or both be respectively-CHO or-CH 2L, L are-OH or good leaving group) preparation R 2And R 6One of be or both are respectively-CHF 2Or-CH 2The structural formula I compound of F.
D) have-the substituent structural formula I of CHO compound by following prepared in reaction:
ⅰ) have-CH(OR 27) 2The selective hydrolysis of the respective compound of substituent structural formula I compound.
R wherein 27Be C 1～C 6Alkyl or two R 27Group formation-CH 2CH 2-segment.
ⅱ) have-CH 2The selective oxidation of the respective compound of the substituent structural formula I of OH compound.
E) pass through R 2And R 6One of be-CH 2Z(Z is good leaving group) the selective hydrolysis of respective compound of structural formula I compound, preparation R 2And R 6One of be-CH 2The structural formula I compound of OH.
F) by from have-respective compound of the structural formula I compound of CH=NOR group (OR be good leaving group) the reaction of cancellation ROH, preparation has-the structural formula I compound of CN base.
G) reductive cleavage or the hydrolysis reaction of the respective compound by structural formula I compound, wherein R 3And R 5Have at least one not to be hydrogen atom or R 2And R 6Have at least one to have carboxylic acid ester groups, preparation structural formula I compound, wherein R 3And R 5Have at least one to be hydrogen atom or R 2And R 6Have one at least and have-the COOH base.
H) esterification of the respective compound by structural formula I compound or transesterification reaction (R wherein 3And R 5Have at least one to be hydrogen atom or R 3Or R 5One of be not the needed group of purpose product, perhaps R 2And R 6Having one at least is-the COOH yl) preparation structural formula I compound, wherein R 3And R 5Have at least one not to be hydrogen atom, perhaps R 2And R 6Have at least one to have carboxylic acid ester groups or 'beta '-ketoester base.
I) selective reduction of passing through the respective compound of structural formula I compound is reacted, wherein R 2And R 6Have at least one to be-CH 2Y(Y is the group that can be reduced to hydrogen), preparation structural formula I compound, wherein R 2And R 3Have at least one to be methyl.
J) remove blocking group in the respective compound by the structural formula I compound that has protected amino, preparation has-NH 2The structural formula I compound of base.
K) (the R wherein of the respective compound by structural formula I compound 3And R 5Have an alkyl that is replaced by good leavings group at least) respectively with structure such as structural formula XI or XII compound or their the change foreign body object or the reaction of piece, preparation structural formula I compound, wherein R 3And R 5Have at least one to be the substituent alkyl that has structure such as structural formula II or III,
Figure 85106878_IMG10
R wherein 11And R 12Structure such as front define,
L) (the R wherein of the respective compound by structural formula I compound 3And R 5Have an alkyl that is replaced by 3-oxa-cyclobutyl at least, this can be replaced this oxa-cyclobutyl by alkyl again on the 3-position) the selective hydrolysis reaction, preparation structural formula I compound, wherein R 3And R 5Has one at least by group-CH(R 36) (CH 2OH)-CH 2The alkyl that OH replaces, R 36Be hydrogen atom or alkyl.
M) pass through R 1Be the C of respective compound of the structural formula I compound of hydrogen atom 1～C 6Alkylation, preparation R 1Be C 1～C 6The structural formula I compound of alkyl.
N) (the R wherein of the respective compound by structural formula I compound 14And R 15One of be-C(=NCN) S alkyl (C 1～C 6) and hydrazine reaction, preparation structural formula I compound, wherein R 14And R 15One of be the group of structural formula IV.
O) (the R wherein of the respective compound by structural formula I compound 14And R 15All be hydrogen atom) with the reaction of ammonia and alkyl aldehydes and alkane diketone (wherein two Sauerstoffatoms are connected on two adjacent carbon atoms), preparation structural formula I compound, wherein R 14And R 15Formation-CR together 16=N-CR 17=CR 18-chain.
P) (the R wherein of the respective compound by structural formula I compound 18Be hydrogen atom) with alkyl isocyanate or have the reaction of the 5-membered ring compounds of good leaving group accordingly, preparation structural formula I compound, wherein R 19Be alkylamino-carbonyl or five-ring.
Q) (the R wherein of the respective compound by structural formula I compound 14And R 15Having one at least is hydrogen atom) and N-cyanoimino=thiocarbonic acid SOH=alkyl (C 1～C 6) the ester reaction, preparation structural formula I compound, wherein R 14And R 15Be the S alkyl (C of group-C(=NCN) 1～C 6).
R) (the R wherein of the respective compound by structural formula I compound 2And R 6Have one at least and have the 'beta '-ketoester base) react preparation structural formula I compound, wherein R with guanidine 2And R 6Have at least one to have substituting group 2-amino-6-hydroxyl-pyrimidine-4-base.
S) by taking structural formula I compound optical isomer intermixture apart, prepare the optical isomer of this compound.
And when needs or when essential, otherwise bar structure formula I compound change into its with the addition piece of the acid of can being used as medicine or.
Method reaction (very synthetic (the Hant of Chinese a) 3Ch Synthesis)) can be warmed up to some temperature to reagent,, under the condition of solvent in the presence of the suitable solvent such as lower alcohol or not, carry out as 20～140 ℃.Method reaction a) comprises:
ⅰ) the reaction of structural formula V compound and structural formula VI and VII compound,
R 4CHO Ⅴ
R 3OOCCH＝C（R 2）NH 2Ⅵ
R 5OOCCH 2COR 6Ⅶ
R wherein 2, R 3, R 4, R 5And R 6Structure such as front define,
ⅱ) the reaction of structural formula VIII compound and structural formula VI compound,
R 4CH＝C（COOR 5）COR 6Ⅷ
R wherein 4, R 5And R 6Structure such as front define,
The reaction of the ⅲ) reaction of structural formula VII, IX and XI V compound, or structural formula VIII, X and XI V compound, or the reaction of structural formula V, VII, X and XI V,
R 4CH＝C（COOR 3）COR 3Ⅸ
At a) ⅲ of method) in, compound (XI V) can exist with the form of piece, as: the caproic acid ammonium.May generate a certain proportion of intermediate product in method in a), hydroxyl-tetrahydropyridine can dewater this intermediate product in certain solvent and increase the productive rate of needed dihydropyridine with dewatering agent, and this solvent shows as inertia under reaction conditions.For example: make dewatering agent with trifluoacetic anhydride, trichloromethane is made solvent.
Method b) reaction can be carried out in the presence of suitable oxygenant, as: a peracetic acid or a chlorine peroxybenzoic acid; Reaction can be carried out in appropriate solvent, as: the mixture of methylene dichloride or methyl alcohol and acetate.
Process c) optimal reaction temperature is-70 °～100 ℃, is reflected at this temperature range and is in the inert halohydrocarbon equal solvent and carries out, with=methyl chloride is good; Fluorizating agent is good with trifluoro sulfuration dialkylamine, as: trifluoro sulfuration diethylamine becomes (2-chloro-1,1,2-trifluoroethyl) diethylamine.Group L can be-OSO 2R x, R wherein xBe C 1～C 6Alkyl, as methyl or right-aromatic bases such as tolyl.
Method d) hydrolysis reaction can with certain aquo acid can with the miscible organic solvent of water in carry out, as (0.5～2.5moles) in acetone or tetrahydrofuran (THF), and temperature of reaction is about-10～50 ℃ with piece acid.Method d) selective oxidation reaction can carry out in the presence of suitable oxygenant, as: pyridine chloro-chromic acid piece.
Method e) hydrolysis reaction can be in the miscible solvent of certain and water (as: diox), and carries out under 25～100 ℃ of temperature ranges.Group Z can be halogen atoms such as fluorine.We are surprised to find: in this reaction, fluorine atom is a good leaving group.
Method f) elimination reaction can be carried out in the presence of the dewatering agent that has no adverse effect of other substituting group in to molecule various, as: excessive acetic anhydride, be dissolved in the sulfurous acid acyl chlorides in the ether or be dissolved in N in the pyridine, N '-dicyclohexyl carbodiimide.-OR base can be 2,4-2,4-dinitrophenoxy base.This reaction can be carried out in 0 °～15 ℃ temperature range according to selected reagent and solvent.If necessary, fat can be formed with known ordinary method on the spot by corresponding formylation compound.
Method g) reductive cleavage reacts available chemical process to be finished, as: add zinc and formic acid.This reaction can should be the inert solvent easily under reaction conditions carries out, as: acetonitrile.As method ⅰ) when comprising hydrolysis reaction, this reaction can be carried out with known ordinary method.
As process h) when comprising esterification, can be with suitable alcohol, preferably excessive alcohol reacts in the presence of dewatering agent, as: dicyclohexyl carbodiimide, also can use chloric acid, imidazoles or mixed anhydride (these mixtures can prepare with known ordinary method).The piece of free acid and compound R 3L or R 5L(L is good ionic groups such as halogen atom) the reaction meeting influential to esterification.Esterification can be carried out in solvent easily, and used solvent should be that ethyl acetate etc. is the inert compound under reaction conditions.Transesterification reaction can use with corresponding sodium alkoxide of the structure of needed ester and reactant in the ester effect get final product.
Method ⅰ) selective reduction reaction can be carried out in the presence of catalyzer such as precious metal.
At method j) in, the protectiveness group can be C 7～C 12Phenylalkyl, C 2～C 6Various groups such as halo acyl group, particularly: benzyl, trifluoroacetyl group or phthalandione imido grpup.Other protectiveness group that everybody is familiar with comprises " the protectiveness group in the organic chemistry " (J.W.F.MeOmic; and " the protectiveness group in the organic synthesis " (T.W.Green, those groups of being introduced in Wiley-Interscience) Plenum Press(1973)).The method of removing the protectiveness group depends on the character of blocking group itself, but normally used be some conventional methods, comprising acid or cracking of alkali formula and hydrogenolysis.
At method k) in, good leavings group can be to groups such as toluenesulphonic acids bases.Reaction can be carried out in the presence of the piece of alkali or structural formula XI or XII compound.Reaction can be carried out in that reaction conditions is in the inert solvent.As: dimethyl formamide or methyl-sulphoxide.
Method l) selective hydrolysis reaction can be carried out under acidic conditions, carries out as being in the inert ethyl acetate equal solvent in the presence of piece acid and to reaction conditions, and temperature of reaction is 0～40 ℃.
Method m) reaction can be selected suitable alkylating reagent for use, under 20 °～100 ℃ temperature ranges, carries out in suitable solvent.Alkylating reagent can be halogenated alkane, preferably alkane iodide; Solvent can be dimethyl formamide or methyl-sulphoxide.This reaction is preferably under the existence of alkali to be carried out, as hydrogen-oxygen for potassium or sodium hydroxide.
Method n) reaction can be carried out in solvent under high temperature (as: reflux temperature), and solvent for use is inertia under reaction conditions, as: alkane chain alcohol such as ethanol.
Method o) reactant is preferably selected symmetric alkane chain diol for use, reaction can be in-10 °～120 ℃ temperature range and methyl alcohol under respective conditions, be in the inert solvent and carry out.
Method p) reaction can be carried out in solvent or under the condition of different solvents.Used solvent should be that chloroform etc. is the inert compound under reaction conditions, and temperature of reaction is about 0 °～120 ℃.Good leavings group can be halogen atoms such as bromine atoms.
Method q) reaction can be in the inert solvent under reaction conditions at alcohol compound (as Virahol) etc. to be carried out.Temperature of reaction is 0 °～4 ℃.
Method r) reaction can be in solvent and no nucleophilicity alkali in the presence of carry out.Used solvent should be inertia under reaction conditions, as making solvent with methyl alcohol.
At process s) in, taking apart of optical activity mixture can be carried out with following method.Work as R 3And R 5During for hydrogen atom, with mixture with have optically active alkali or have optically active alcohol (as: CCl 3(C 6H 5) CHOH or C 6H 5(OCH 3) CHCH 2OH) ester effect forms piece; Work as R 3And R 5During for aminoalkyl group, with mixture with have optically active acid effect when forming piece.Can separate these pieces with the method for selective crystallization then, preferably use high performance liquid chromatography (HPLC) to separate these pieces.Piece after the separation can be used method g) or square h) method change them into needed optically active acid or ester.
All reactant or known in the aforesaid method, or can be by the currently known methods preparation of known compound by a step or multistep.
Some compounds of structure such as structural formula V are novel.Therefore the present invention also provides such structural formula V compound, wherein R 4Be that three, four substituent phenyl are arranged, these substituting groups can be: CF 3, XR 22, nitro, halogen atom, CN, C 1～C 6Alkyl, formyl radical, oxalic acid base ,-NCR 23) COR 24,-CONR 35R 26And by the amino of benzenesulfonyl or trifluoroacetyl group replacement.If R 4Not 2,3-two chloro-6-fluorophenyls, 3-chloro-6-fluoro-2-trifluoro tetramethylphenyl or 2,3,5,6-tetrafluoro phenyl, then R 4In be connected R 4Have F or CF on the atom adjacent with the atom of-CHO 3Substituting group.
The be used as medicine piece that has the structural formula I compound of basic group comprises and contains anionic of nontoxic organic or inorganic, for example the piece that forms with piece acid or toxilic acid.
The structural formula I compound and the piece that can be used as medicine thereof are applied because of having pharmacological action in animal body.More particularly, they can stop calcium intravasation and cardiac muscle, thereby bring high blood pressure down, myocardial contraction changes and heart rate.
Structural formula I compound can supply the usefulness of the following disease of treatment: renal vascular disease, malignant hypertension or essential hypertension (comprising the essential hypertension crisis), lung's high pressure, vasospasm stenocardia, chronic stable angina pectoris and congestive heart failure.Can also be used for following treatment of diseases in addition: renal failure, arrhythmia, hypertrophic cardiomyopathy, cerebrovascular disease (comprise cerebral hemorrhage, local asphyxia and vasospasm, migraine, high altitude disease and hearing are lost total), property vascular disease in periphery (comprise the Reynolds syndrome, intermittent timpang, toe ulcer).Also can in surgical operation, do the cardiac anesthesia agent, as the cardiopulmonary bypass surgery, myocardial infarction and local asphyxia and treatment and prevent.
In above-mentioned application, using dosage is generally per kilogram of body weight 0.1～10mg every day.For the people, the dosage of every day is about 5～500mg, and 5～200mg is comparatively suitable, 5～100mg the best.These dosage perhaps are divided into 1～200mg portion to supply with to good once a day, preferably 2～25mg portion, i.e. 2～4 supplies every day.
Structural formula I compound also can be used as intermediate and is used for the preparation that other has the compound of pharmacologically active.
Structural formula I compound is compared with the known compound that other has analog structure, has superiority.
Structural formula I compound can by oral, snuffing, vein, muscle, peritoneal injection or surgical operation implant enter lung, chamber before, oesophagus, rectum, local cortex, other surface of eyes and health.
R 1Being that methyl is more suitable, is that H is best.
R 2Can be CN, CHO or the C that replaced by halogen atom such as fluorine or hydroxyl 1～C 6Alkyl, whether replace that to reach the position of substitution be selectable.
R 2Be CH 3More suitable, be FCH 2Best.
R 3And R 5Has (a R preferably at least 3) be C 1～C 6Alkyl, for example: methyl, ethyl, 1-methylethyl or 2-methyl-propyl.
Work as R 3Or R 5During the alkyl that selectively replaced, straight chain or have the CC of side chain preferably 1～C 6Alkyl.
Work as R 3Or R 5Be or contain quaternary, five yuan or hexavalent O, N ,-S(O) n-heterocycle the time, this heterocycle preferably: 3-thia cyclobutyl, 3-thia cyclobutyl-S, S-dioxy, 3-thia cyclobutyl-S-oxygen, 3-sulphur oxa-cyclobutyl, 4-tetrahydrofuran base or 3-azetidine base.The group that replaces selectively on the heterocycle is as there being C such as methyl on the 3-position 1～C 6Alkyl.
Work as R 3Or R 5Be or when containing cycloalkyl or cycloalkenyl group, they are the hydrocarbon of three, four or five carbon atoms preferably, and by C such as methyl 1～C 6Alkyl selectively replace.When cycloalkyl linked to each other with alkyl, this alkyl is methyl preferably.Two cycloalkyl are linked to each other with alkyl (as methyl).In the time of when cycloalkyl and on phenyl ring, it can be 2, and 3-dihydro-2-pitches base; When cycloalkyl formed the key bridge, it can be octahydro-bridge-2-pentalenyl.
Work as R 3Or R 5When containing structural formula II or III group, R 11And R 12Preferably toluene or phenyl, structural formula II or III group preferably are connected on the hexamethylene group.
Work as R 2Or R 5During the alkyl that replaced by halogen atom, this halogen atom can be a chlorine, but fluorine preferably.
Work as R 2Or R 5During the alkyl that replaced by alkylamino, this alkylamino is alkyl-(phenylalkyl) amino preferably, as: methyl-(benzyl) amino.
R 6Can selectively be inserted by O and by halogen atom, 2-amino-6-hydroxy pyrimidine-4-base or-NR 14R 15The C of Qu Daiing selectively 1～C 6Alkyl.
R 16, R 17And R 18Methyl preferably.
R 19Preferably hydrogen, right-halogen-(as: right-the benzyl chloride base) ,-CONHCH 3Or 2-thiazolyl.
R 6The amino butyl of methyl, a methyl fluoride, (2-amino ethoxy) methyl or 4-preferably.
R 4Structure preferably as structural formula X III.
R wherein 7Be trifluoromethyl, thiophenyl, fluorine atom, benzenesulfonyl, NO 2Or chlorine.
Figure 85106878_IMG11
R 8Be itrile group, chlorine atom, fluorine atom, thiophenyl, methylthio group, phenylsulfonamido, trifluoroacetyl group, trifluoromethyl, methoxyl group, rosickyite base, nitro or amino.
R 9Be H, F or Cl.
R 10Be H, F, methoxyl group or chlorine atom.
Should particularly point out: R 7And R 10All not that chlorine atomic time effect is better, if R 7, R 8And R 10Not that hydrogen atom is then better.R 7Be trifluoromethyl, R 8Be chlorine atom or itrile group, R 9Be hydrogen atom, R 10Compound the best when being fluorine atom.
Work as R 4When being heterocyclic group, heterocycle is aromaticity preferably, and heteroatoms with connect R 4Adjacent with the atom of molecule other parts.
Compound preferably contains following groups: R 1Be hydrogen atom, R 2Be methyl fluoride or methyl, R 3Be methyl, R 5Be 3-thia cyclobutyl, 1-methylethyl, cyclobutyl, 3-thia cyclobutyl-S, S-dioxy, 6-(5-phenyl-3-pyrazolyl oxygen) n-hexyl, cyclopropyl methyl, 6-((6-methyl-2-phenyl-4-pyrimidyl) oxygen) n-hexyl or ethyl, R 6Be methyl or (2-amino ethoxy) methyl, R 4Be 3-nitro-2-thiophene grace base, or structural formula XII I group, wherein R 7Be trifluoromethyl, R 8Be chlorine atom or itrile group, R 9Be hydrogen atom, R 10It is fluorine atom.
Concrete feature of the present invention is R 4Substituting group type around the group.
According to the present invention, we also provide one to contain structural formula I compound or can be used as medicine piece and medicinal auxiliary, the medical mixture of the mixture of diluent or carrier.
To the present invention be described with specific examples below, but the present invention is not only limited to these examples.Temperature in the example is all with a ℃ office.
Example 1:
4-(3-cyano group-6-fluoro-2-(trifluoromethyl) phenyl)-and the 2-(methyl fluoride)-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid-3-thia ring butyl ester.
With 4-fluoro-3-formyl radical-2-trifluoromethyl benzonitrile (1.6g; 7.4mmoles), (1.0g is 7.4mmoles) with 3-amino-2-butylene acid-3-thia ring butyl ester (1.27g for 4-fluoro-3-ketobutyric acid methyl esters; 7.4mmoles) be dissolved in the anhydrous butyl alcohol-tert of 40ml, be heated to 45 °.Keep under the nitrogen atmosphere boiling off solvent two days later, be dissolved in residue in the 40ml methylene dichloride and add the 0.3ml trifluoacetic anhydride.After 10 minutes solvent evaporation is fallen, residue carries out purifying with chromatogram, and (carrier is a silicon, 60～80 ° of ethyl acetate/petroleum ether) mixture is an eluant), crystallization just obtains 0.9g example name compound, the yellow crystal thing that fusing point is 203～204 ° in 2-propyl alcohol/methylene dichloride/sherwood oil (60～80 °) mixture.
Example 2:
4-(3-chloro-6-fluoro-2(trifluoromethyl) phenyl-1,4-dihydro-2,6-dimethyl pyrazole pyrrole-3-methyl-formiate-5-formic acid-1-methyl ethyl ester.
With 3-amino-2-butylene isopropyl propionate (3g, 21mmoles), 3-ketobutyric acid methyl esters (2.26ml, 21mmoles) with 3-chloro-6-fluoro-2-(trifluoromethyl) (4.7g 21mmoles) is dissolved in the anhydrous butanols of 40ml phenyl aldehyde, is heated to 60 °, keep after 36 hours, chilled solution is concentrated under vacuum, then circumstances in which people get things ready for a trip spectrum purifying (with silicon is carrier, and the dichloromethane solution of 2% ethyl acetate is an eluant).
(silicon is carrier with high pressure liquid chromatography, the mixture of sherwood oil, ethyl acetate and methylene dichloride (5: 1: 5) is an eluant) be further purified, recrystallization just obtains 0.8g example name compound, 154～156 ° of fusing points in sherwood oil (60～80 °)/acetone mixture.
Example 3:
The 2-(methyl fluoride)-1, Nicotinicum Acidum methyl esters-5-isopropyl ester 4-dihydro-6-methyl-4(3-nitro-2-thiophene grace base).
With 3-nitro-2-thiophene carbonyl aldehyde (0.735g, 5mmoles), 4-fluoro-3-ketobutyric acid methyl esters (0.67g, 5mmoles) with 3-amino-2-butylene acid-1-methyl ethyl ester (0.715g, (with silicon is carrier to mixture 5mmoles), crystallization, recrystallization in the 2-propyl alcohol again in ether/sherwood oil (60～80 °) with chromatogram purification, just obtain 0.15g example name compound, 123～124 ° of fusing points.
Example 4:
4-(3-cyano group-6-fluoro-2-trifluoromethyl)-and the 2-(methyl fluoride)-1,4-dihydro-6-picoline-3-methyl-formiate-5-isopropyl formate.
With 4-fluoro-3-formyl radical-2-trifluoromethyl benzonitrile (1.57g; 7.23mmoles); 3-amino-2-butylene acid-1-methyl ethyl ester (1.03g; 7.23mmoles) and 4-fluoro-3-ketobutyric acid methyl esters (0.9g; 7.23mmoles) be dissolved in the 50ml butanols; be heated to 45 °; keep after 7 days under the nitrogen atmosphere; boil off solvent; residue is with chromatogram purification (with silicon is carrier, and ethyl acetate/petroleum ether (60～80 °) mixture is an eluant), recrystallization in the 2-propyl alcohol; just obtain 0.74g example name compound, 154～155 ° of fusing points.
Example 5:
4-(3-cyano group-6-fluoro-2-trifluoromethyl)-and 2-fluoro methyl isophthalic acid, 4-dihydro-6-picoline-3-methyl-formiate-5-formic acid ring butyl ester.
With 4-fluoro-3-formyl-2-trifluoromethyl benzonitrile (1.1g, 5.1mmoles), 3-amino-2-butylene acid ring butyl ester (0.79g, 5.1mmoles) and 4-fluoro-3-ketobutyric acid methyl esters (0.67g, 5.1mmoles) be dissolved in the 25ml butyl alcohol-tert, be heated to 45 °, keep under the nitrogen atmosphere boiling off solvent after 3 days, residue is dissolved in the 10ml toluene and adds the 0.3ml trifluoacetic anhydride, stir after five minutes, add 10ml methyl alcohol, then solvent is boiled off, residue is crystallization purifying in 2-propyl alcohol/dichloromethane mixture, then with chromatogram be further purified (be carrier with silicon, ethyl acetate/petroleum ether (60～80 °) *Be eluant), in 2-propyl alcohol/sherwood oil (60～80 °) mixture, carry out recrystallization again and just obtain 0.56g example name compound.188～189 ° of fusing points.
Example 6:
4-(3-chloro-6-fluoro-2-(trifluoromethyl) phenyl)-and 2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid-(3-thia cyclobutyl-S, S-dioxy) ester.
With 3-ketobutyric acid-(3-thia cyclobutyl-S, the S-dioxy) ester (1.5g, 7.3mmoles) and ammonium acetate (0.56g, 7.3mmoles) be dissolved in the 25ml butyl alcohol-tert, be heated to 55 °, keep after 1 hour, add 3-chloro-6-fluoro-2-trifluoromethyl aldehyde (1.65g, 7.3mmoles) and 4-fluoro-3-ketobutyric acid methyl esters (0.98g 7.3mmoles) is heated to 55 °, reacts after 4 days, boil off solvent, (with silicon is carrier to residue, and crystallization in ethyl acetate/petroleum ether (60～80 °) mixture just obtains the complex compound (1: 1) of 0.65g example name compound and ethyl acetate with chromatogram purification.110～112 ° of fusing points.
Example 7:
4-(3-cyano group-6-fluoro-2-(trifluoromethyl) phenyl)-and 2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid-6-(5-phenyl-3-pyrazoles oxygen) just own ester.
With 3-ketobutyric acid-6-(5-phenyl-3-pyrazoles oxygen) just own ester (1.31g; 3.8mmoles); ammonium acetate (0.29g; 3.8mmoles) and the 40ml butyl alcohol-tert be heated to 50 °; keep after 6 hours; add 4-fluoro-3-formyl radical-2-4-trifluoromethylbenzonitrile (0.8g; 3.7mmoles) and 4-fluoro-3-ketobutyric acid methyl esters (0.55g; 4.1mmoles) butyl alcohol-tert (35ml) solution; 50 ° after following 2 days; boil off solvent, be dissolved in residue in the 50ml methylene dichloride and add the 0.4ml trifluoacetic anhydride, room temperature is after following 15 minutes; add 5ml methyl alcohol; solvent evaporation is fallen the back with behind chromatogram (* 2) purifying (eluant is ethyl acetate/petroleum ether (60～80 °), ethyl acetate/dichloromethane), and crystallization just obtains 0.2g example name compound in normal hexane.126～130 ° of fusing points.
The compound of example 8～22 is by the method preparation of example 1 and example 5.
Example 8～22:
8:4-(3,6-two fluoro-2-thiophenyl phenyl)-the 2-Trifluoromethyl-1,4-dihydro-6-picoline-3-methyl-formiate-5-isopropyl formate.93～95 ° of fusing points (2-propyl alcohol).
9:4-(3,6-two fluoro-2-Trifluoromethyl-1s, 4-dihydro-6-picoline-3-methyl-formiate-5-formic acid ring butyl ester.147～149 ° of fusing points (hexanaphthene).
10:4-(2,5-two fluoro-3-thiophenyl phenyl)-2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-isopropyl formate.149～151 ° of fusing points (hexanaphthene).
11:4-(3-cyano group-6-fluoro-2-trifluoromethyl)-and 2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid ring pentyl ester.154～156 ° of fusing points (2-propyl alcohol/sherwood oil (60～80 °)).
12:4-(3-cyano group-6-fluoro-2-trifluoromethyl)-and 2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid-2-cyano group ethyl ester.165～166 ° of fusing points (methylene dichloride/2-propyl alcohol/hexanaphthene).
13:4-(3-cyano group-6-fluoro-2-trifluoromethyl)-and 2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid-2-methyl propyl ester.151～152 ° of fusing points (hexanaphthene).
14:2-methyl fluoride-4-(6-fluoro-3-methylthio group-2-trifluoromethyl)-1,4-dihydro-6-picoline-3-methyl-formiate-5-isopropyl formate.111～112.5 ° of fusing points (hexanaphthene).
15:2-methyl fluoride-4-(6-fluoro-3-benzene sulfonyl) phenyl amino-2-(trifluoromethyl))-1,4-dihydro-6-picoline-3-methyl-formiate-5-isobutyl carbonate propyl ester.132～134 ° of fusing points (2-propyl alcohol/acetone/sherwood oil (60～80 °)).
16:2-methyl fluoride-4-(6-fluoro-3-(2,2, the 2-trifluoroacetyl) amino)-the 2-(trifluoromethyl) phenyl)-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid-1-methyl ethyl ester.Fusing point: 197 °～198 ° (2-propyl alcohol).
17:4-(6-fluoro-2,3-pair-trifluoromethyl)-2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-isopropyl formate.Fusing point: 112～113 ° (sherwood oil (60～80 °)).
18:4-(6-fluoro-3-methoxyl group-2-(trifluoromethyl) phenyl)-and 2-chloromethyl-1,4-dihydro-6-picoline-3-methyl-formiate-5-isopropyl formate.159～160 ° of fusing points (sherwood oil (60～80 °)).
19:2-methyl fluoride-4-(6-fluoro-3-rosickyite base-2-trifluoromethyl)-1,4-dihydro-6-picoline-3-methyl-formiate-5-isopropyl formate.124～126 ° of fusing points (normal hexane).
20:4-(2,6-two fluoro-3-oil of mirbane)-2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid ring butyl ester.142 143 ° of fusing points (methylene dichloride/2-propyl alcohol/sherwood oil (60～80 °)).
21:4-(3-cyano group-2, the 6-difluorophenyl)-2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid Virahol.Fusing point: 144～146 ° (2-propyl alcohol/sherwood oil (60～80 °)).
22:4-(3-chloro-6-methoxyl group-2-trifluoromethyl)-and 2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-isopropyl formate.Fusing point: 150～151 ° (2-propyl alcohol/sherwood oil (60～80 °)).
The compound of example 23～35 is by the method preparation of example 2 and 4.
23:1,4-dihydro-2,6-dimethyl-4-(2,3,5,6-tetrafluoro phenyl)-3,5-dinicotinic acid methyl esters.Fusing point: 178 °～179 ° (2-propyl alcohol).
24:4-(3-chloro-6-fluoro-2-trifluoromethyl)-1,4-dihydro-2,6-dimethyl-3,5-dinicotinic acid methyl esters.243 ° of fusing points (acetone/sherwood oil (60～80 °)).
25:2-methyl fluoride-1,4-dihydro-6-methyl-4-(2,4,5-three chloro-3-thiophene grace bases) Nicotinicum Acidum methyl esters-5-isopropyl formate.Fusing point: 102～104 ° (sherwood oil (60～80 °)).
26:4-(3,6-two fluoro-2-benzenesulfonyl phenyl)-2-fluorophenyl-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid Virahol.Fusing point: 192～193 ° (butyl alcohol-tert).
27:4-(3-chloro-6-fluoro-2-trifluoromethyl)-1,4-dihydro-2,6-dimethyl-3,5-dinicotinic acid isopropyl ester.Fusing point: 70 ° of sherwood oils (60～80 °)).
28:4-(3,6-two fluoro-2-trifluoromethyls)-2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid-(3-thia cyclobutyl) ester.Fusing point: 63～65 ° (2-propyl alcohol/normal hexane).
29:4-(3,6-two fluoro-2-trifluoromethyls)-2-methyl fluoride-1,4 dihydro-6-picoline-3-methyl-formiate-5-formic acid-(3-thia cyclobutyl) ester.Fusing point: 148～149 ° (hexanaphthene).
30:4-(3-cyano group-6-fluoro-2-trifluoromethyl)-and 2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid-(3 methyl-3-thia cyclobutyl) methyl esters.Fusing point: 176～177 ° (ethyl acetate/normal hexane).
31:4-(3-(1,3-dioxolane-2-yl)-2-thiophene grace base)-2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-isopropyl formate.Fusing point: 114 °～116 ° (sherwood oil (60～80 °)).
32:4-(2,6-two fluoro-3-nitrophenyls)-2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-isopropyl formate.Fusing point: 134～136 ° (sherwood oil (60～80 °)).
33:4-(3-chloro-6-fluoro-2-nitrophenyl)-and 2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-isopropyl formate.Fusing point: 123～125 ° (acetone/sherwood oil (60～80 °)).
34:4-(3,5-dihydro-2-fluoro-6-trifluoromethyl)-2-methyl fluoride-1,4-dihydro-6-methylpyrimidine-3-methyl-formiate-5-isopropyl formate.Fusing point: 174～175 ° (butyl alcohol-tert).
35:4-(3,6-two chloro-2-trifluoromethyls)-2-methyl fluoride-1,4-dihydro-6-methylpyrimidine-3-methyl-formiate-5-isopropyl formate.M +483/5/7; Nuclear magnetic resonance spectrum: (CDCl 3) δ 3.6(S, 3H) and 2.4(S, 3H).
The method of example 3 is used for the preparation of example 36～45 compounds.
36:4-(2,3-two chloro-6-fluorophenyls)-1,4-dihydro-2,6-diformazan pyrimidine-3,5-dioctyl phthalate ethyl ester.Fusing point: 144～146 °; Softening temperature 139(sherwood oil (60～80 °)).
37:4-(3-chloro-6-fluoro-2-trifluoromethyl)-1,4-dihydro-2,6-lutidine-3,5-dioctyl phthalate ethyl ester.Fusing point: 135～137 ° (sherwood oil (60～80 °)).
38:4-(4,5-two chloro-3-thiophene grace bases)-2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-isopropyl formate.Fusing point: 121～122 ° (2-propyl alcohol).
39:2-methyl fluoride-1,4-dihydro-6-methyl-4-(3-methyl-2-thienyl) Nicotinicum Acidum methyl esters-5-isopropyl formate.Fusing point: 96～98 ° (2-propyl alcohol).
40:4-(3,6-two fluoro-2-trifluoromethyls)-2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-isopropyl formate.Fusing point: 125～126 ° (normal hexane).
41:2-methyl fluoride-4-(6-fluoro-3-nitro-2-trifluoromethyl)-1,4-dihydro-6-picoline-3-methyl-formiate-5-isopropyl formate.Fusing point: 184～185 ° (2-propyl alcohol/normal hexane).
42:4-(2,5-two fluoro-3-trifluoromethyls)-2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-isopropyl formate.Fusing point: 143～145 ° (normal hexane).
43:4-(2-chloro-6-fluoro-3-nitrophenyl)-and 2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-isopropyl formate.Fusing point: 159～161 ° (acetone/sherwood oil (60-80 °)).
44:2-methyl fluoride-1,4-dihydro-6-methyl-4-(2,3,6-trifluoromethyl) Nicotinicum Acidum methyl esters-5-isopropyl formate.Fusing point: 111～113 ° (sherwood oil (60～80 °)).
45:4-(2,5-two chloro-3-trifluoromethyls)-2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-isopropyl formate.Fusing point: 158～159 ° (sherwood oil (60～80 °)).
The method of example 6 is used for the preparation of the compound of example 46～50.
46:4-(3-chloro-6-fluoro-2-trifluoromethyl)-and 2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid (3-methyl-3-oxa-cyclobutyl) methyl esters.Fusing point: 170～171 ° (2-propyl alcohol).
47:4-(3-chloro-6-fluoro-2-trifluoromethyl)-and 2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid two cyclopropyl methyl esters.Fusing point: 121～122.5 ° (sherwood oil (40～60 °)).
48:4-(3-cyano group-6-fluoro-2-trifluoromethyl)-and 2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid (3-methyl-3-oxa-cyclobutyl) methyl esters.Fusing point: 198～200 ° (2-propyl alcohol/sherwood oil (60～80 °)).
49:4-(3-cyano group-6-fluoro-2-trifluoromethyl)-and 2-methyl fluoride-1,4-dihydro-6-methyl-3-methoxycarbonyl-5-(3-oxa-cyclobutoxy group carbonyl pyridine.Fusing point 209-10 ℃ (2-propyl alcohol/acetone/methylene dichloride).
50:(E) 4-(3-chloro-6-fluoro-2-(trifluoromethyl) phenyl-2-(methyl fluoride) 1,4-dihydro-6-methyl-3-methoxycarbonyl-5(4-cyclopropyl-3-butyl) oxygen base carbonyl pyridine.Fusing point: 110-2 ℃ of (sherwood oil (40-60.））
The method of example 7 is used for the preparation of example 51 compounds.
51:4-(3,6-two fluoro-2-trifluoromethyls)-2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid-(3-oxa-cyclobutyl) ester: fusing point: 163～164 ℃ (sherwood oil (60～80 °)).
Example 52:
4-(2,3-two chloro-6-fluorophenyls)-1,4-dihydro-2,6-lutidine-3-methyl-formiate-5-ethyl formate.
With 2,3-two chloro-6-fluorobenzaldehydes (1.93g, 10mmoles), 3-oxidation ethyl butyrate (1.27ml, 10mmoles),
Figure 85106878_IMG12
The mixture of pyridine (0.01ml) and n-caproic acid (0.03ml) is dissolved in the 150ml benzene in fourth and Rodney Stark device (Dean and Stark Apparatus), is heated to reflux temperature, keeps after 2 hours and 4 hours, adds 0.01ml
Figure 85106878_IMG13
Pyridine and 0.03ml n-caproic acid continue reaction 30 minutes.Cooled solution piece water, saturated sodium bicarbonate and piece water washing, and use dried over sodium sulfate, under vacuum, solvent is removed then, stay the 2-(2 of 3.1g yellow oily, 3-two chloro-6-fluorophenyls) methylene)-ethyl 3-oxobutanoate.This oily matter is dissolved in the 12ml butyl alcohol-tert, and adding 3-amino-2-butylene acid methyl esters (1.15g, 10mmoles).Room temperature after following six days is removed solvent, residue with chromatogram purification (make carrier with silicon, ethyl acetate/petroleum ether (60～80 °) mixture is made eluant) after, recrystallization just obtains 1 gram example name compound in the 2-propyl alcohol.Fusing point: 167～168 ℃.
Example 53:
4-(3-chloro-6-fluoro-2-(trifluoromethyl) phenyl-2-(methyl fluoride)-1,4-dihydro-6-first pyridinium hydroxide-3-methyl-formiate-5-formic acid-(3-thia cyclobutyl) ester.
With phosphorus pentachloride (2.1g 0.01mmoles) under agitation is added to 4-(3-chloro-6-fluoro-2-(trifluoromethyl) phenyl)-6-methyl fluoride-1,4-two chloro-5-methoxycarbonyl-2-methyl-3-pyridine carboxylic acid
(4.25g is in methylene dichloride 0.01mmoles) (250ml) solution.(1.8g 0.02mmoles), and under agitation placed this mixture 16 hours to add 3-thia cyclobutanol after 4 hours.Stir and add aqueous sodium carbonate down, after 2 hours organic matter layer is wherein told, use the piece water washing, after dried over mgso, boil off flux, sherwood oil (60～80 °) is added drop-wise in the residue, solids recrystallization in sherwood oil (60～80 °) of separating out is just obtained 0.21g example name compound.137～139 ° of fusing points.
Example 54:
4-(3-cyano group-6-fluoro-2-trifluoromethyl)-and 2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid-(3-thia cyclobutyl) ester.
With phosphorus pentachloride (0.5g 2.4mmoles) under agitation is added to 4-(3-cyano group-6-fluoro-2-trifluoromethyl)-6-methyl fluoride-1,4-dihydro-5-methoxycarbonyl-2-methyl-3-pyridine carbonic acid
(1g is in methylene dichloride 2.4mmoles) (80ml).Stir after 3 hours, add 0.432g3-thia cyclobutanol, and under agitation placed 25 hours, under agitation add aqueous sodium carbonate then, after 1 hour the piece water washing is told and used to organic matter layer, dried over mgso (is made carrier with silicon with chromatogram purification after boiling off solvent, ethyl acetate/petroleum ether (60～80 °) is made eluant), crystallization just obtains 0.27g example name compound in acetone/sherwood oil (60～80 °).Fusing point: 207～208 °
Example 55:
4-(3-cyano group-6-fluoro-2-trifluoromethyl)-and 2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid cyclopropyl methyl esters.
With phosphorus pentachloride (0.5g, 2.4mmoles) under agitation be added to 4-(3-cyano group-6-fluoro-2-trifluoromethyl)-6-methyl fluoride-1, (1.0 grams are in anhydrous methylene chloride 2.4mmoles) (30ml) solution for 4-dihydro-5-methoxycarbonyl-2-methyl-3-pyridine carbonic acid.(0.25g 3.6mmoles), after 4 hours, pours this reaction mixture stirring in the aqueous sodium carbonate into again, stirs after 10 minutes, and organic matter layer is told, and uses dried over mgso to stir adding cyclopropane methyl alcohol after 1 hour.After solvent evaporation fallen, residue crystallization in 2-propyl alcohol/methylene dichloride just obtained 0.58g example name compound.184～185 ° of fusing points
The compound of example 56～60 is prepared by suitable reactant by the method for example 53～55.
56:4-(3-chloro-6-fluoro-2-trifluoromethyl)-and 2-methyl fluoride-1,4-dihydro-6-methyl-3-methoxycarbonyl-5-cyclobutoxy group carbonyl pyridine.169～70 ° of fusing points (2-propyl alcohol/hexanaphthene).
57:4-(3-chloro-6-fluoro-2-trifluoromethyl)-and 2-methyl fluoride-1,4-two chloro-6-picolines-3-methyl-formiate-5-formic acid ring third methyl esters.160～161 ° of fusing points (2-propyl alcohol/hexanaphthene).
58:4-(3,6-two fluoro-2-trifluoromethyls)-2-methyl fluoride-1,4-two chloro-6-picolines-3-methyl-formiate-5-formic acid cyclopropyl methyl esters.Fusing point: 140～141 ° (hexanaphthene).
59:4-(3-cyano group-6-fluoro-2-trifluoromethyl)-and 2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid-1-methyl cyclopropyl methyl esters.Fusing point: 157～158 ° (2-propyl alcohol/methylene dichloride/sherwood oil (60～80 °)).
60:4-(3-chloro-6-fluoro-2-trifluoromethyl)-and 2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid-2-methyl-benzyl amino ethyl ester.Fusing point: 110 °～111 ℃ (2-propyl alcohol/normal hexane).
Example 61:
4-(3-chloro-6-fluoro-2-trifluoromethyl)-1,4-dihydro-2,6-lutidine-3-methyl-formiate-5-formic acid-6-(5-phenyl-3-pyrazoles oxygen) just own ester.
4-(3-chloro-6-fluoro-2-trifluoromethyl)-2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid-6-(5-phenyl-3-pyrazoles oxygen) just own ester (1.05g, 1.57mmoles) be dissolved in and contain 5%pd/c(0.5g) and 35ml methyl alcohol in, under room temperature, 1 normal atmosphere, carry out hydrogenation.Then catalyzer is leached, boil off solvent.Residue with chromatogram (with silicon is carrier, and ethyl acetate/normal hexane mixture is made eluant) purifying after, crystallization just obtains 0.47g example name compound in ethyl acetate/hexanaphthene mixture.Fusing point: 194～195 °
The compound of example 62～68 is by the suitable reactant preparation of example 61.
62:4-(3-cyano group-6-fluoro-2-trifluoromethyl)-1,4-dihydro-2,6-lutidine-3-methyl-formiate-5-formic acid-6-(5-phenyl-3-pyrazoles oxygen) just own ester.Fusing point: 175～177 ° (ethyl acetate/hexanaphthene/normal hexane).
63:4-(3-cyano group-6-fluoro-2-trifluoromethyl)-1,4-dihydro-2,6-lutidine-3-methyl-formiate-5-isopropyl formate.Fusing point: 188～189 ° (sherwood oil (60～80 °)).
64:4-(3,6-two fluoro-2-trifluoromethyls)-1,4-dihydro-2,6-lutidine-3-methyl-formiate-5-formic acid ring butyl ester.Fusing point: 181～183 ° (2-propyl alcohol/sherwood oil (60～80 °)).
65:4-(3-cyano group-6-fluoro-2-trifluoromethyl)-1,4-dihydro-2,6-lutidine-3-methyl-formiate-5-formic acid ring butyl ester.Fusing point: 204～205 ° (2-propyl alcohol/sherwood oil (60～80 °)).
66:4-(3,6-two fluoro-2-trifluoromethyls)-1,4-dihydro-2,6-lutidine-3-methyl-formiate-5-formic acid-6-(5-phenyl-3-pyrazoles oxygen) just own ester.Fusing point: 154～156 ° (ethyl acetate/hexanaphthene).
67:4-(3-chloro-6-fluoro-2-trifluoromethyl)-1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-5-(2-(methyl (benzyl) amino) oxyethyl group) carbonyl pyridine.
60～62 ° of fusing points (2-propyl alcohol/normal hexane).
68:4-(3-chloro-6-fluoro-2-trifluoromethyl)-1,4-dihydro-2,6-lutidine-3-methyl-formiate-5-formic acid-6-(5-methyl-3-pyrazoles oxygen) just own ester.158～160 ° of fusing points (ethyl acetate/hexanaphthene/normal hexane).
Example 69:
4-(3-chloro-6-fluoro-2-trifluoromethyl)-1,4-two chloro-2-methylols-6-picoline-3-methyl-formiate-5-isopropyl formate.
2.0g4-(3-chloro-6-fluoro-2-trifluoromethyl)-1, it is that 7 damping fluid (Sodium phosphate dibasic 123.3g) solution 70ml and 3.46g citric acid are dissolved in the 1000ml water that 4-dihydro-2-methyl fluoride-6-picoline-3-methyl-formiate-5-isopropyl formate is dissolved in 140ml diox and PH) in, be heated to reflux temperature, kept 36 hours.Chilled solution is poured into second joins in ethyl ester/water mixture.Isolate organic matter layer, use dried over mgso, after boiling off solvent, at 0 ℃ of following drip dichloromethane, filter and obtain 0.55g4-(3-chloro-6-fluoro-2-trifluoromethyl)-1,4,5,7-tetrahydrochysene-2-methyl-5-oxo furans (3,4-b) Nicotinicum Acidum isopropyl ester, fusing point is greater than 250 °.Methylene dichloride in the filtrate is evaporated, and residue recrystallization in acetone/sherwood oil (60～80 °) just obtains 1.2g example name alcohol.127～129 ° of fusing points.
Example 70:
4-(3-chloro-6-fluoro-2-trifluoromethyl)-and 2-formyl radical-1,4-dihydro-6-picoline-3-methyl-formiate-5-isopropyl formate.
20ml is dissolved with 4-(3-chloro-6-fluoro-2-trifluoromethyl)-1,4-dihydro-2-methylol-6-picoline-3-methyl-formiate-5-isopropyl formate (1.2g, 2.6mmoles) dichloromethane solution be added to pyridine chloro-chromic acid piece (0.84g be in methylene dichloride 3.9mmoles) (80ml) solution.This mixture stirs and adds the 100ml ether after 1.75 hours, elimination solids then, and filtrate is passed through with the washed well active magnesium silicate pillar of ether, steaming vibrating dichloromethane/ether again, residue (is made carrier with silicon with chromatographic separation, ethyl acetate/petroleum ether (60～80 °) is made eluant) after, crystallization just obtains 0.16g example name compound in sherwood oil (60～80 °).Fusing point: 118～119 °
Example 71:
4-(3-chloro-6-fluoro-2-trifluoromethyl)-and 2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid-(3-thia cyclobutyl-S, S-dioxy) ester.
3-chlorine peroxybenzoic acid (0.39g, 2.3mmoles) be added to 4-(3-chloro-6-fluoro-2-difluoromethyl phenyl)-2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5 formic acid thia ring butyl ester (0.25g, 0.5mmoles) methylene dichloride (25ml) solution in, after stirring 16 hours, add the aqueous solution of saturated sodium bicarbonate.After 15 minutes organic matter layer is isolated, and with sodium metabisulfite liquation and piece water washing, dried over mgso is fallen solvent evaporation then, (silicon is made carrier to residue, and crystallization just obtains example name sulfone (0.03g) in the ethyl acetate/petroleum ether (bp60～80 °) with chromatogram.Fusing point: 174.5～176 °.
Example 72:
4-(3-chloro-6-fluoro-2-trifluoromethyl)-and 2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid-(cis-3-thia cyclobutyl-S-oxygen) ester.
Under 0 ℃ and the agitation condition, at 4-(3-chloro-6-fluoro-2-trifluoromethyl)-2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid thia ring butyl ester (0.6g, 1.2mmoles) trichloromethane (50ml) solution in add 3-chlorine peroxybenzoic acid (0.34g, 2mmoles).This reaction when not having reactant thia ring butyl ester in the system, just adds saturated sodium bicarbonate aqueous solution with the thin-layer chromatography monitoring.After 30 minutes organic matter layer is isolated,, used dried over mgso with sodium sulfite solution and piece water washing.Then solvent evaporation is fallen.Tetrahydrofuran (THF)/normal hexane is made washings HPLC separating isomerism body, isomer recrystallization in acetone/sherwood oil (60～80 °) that elder generation's drip washing goes out, obtain containing crystallisate 0.104 gram of 0.5mmoles acetone, 179～181 ° of its stereochemical structures of fusing point are " cis ".Another isomer is recrystallization in acetone/sherwood oil (60～80 °) mixture, obtains the crystallisate that 0.24 gram contains 0.5mmoles acetone, and 168～170 ° of fusing points, its stereochemical structure are " reaction ".
Example 73:
4-(3-chloro-6-fluoro-2-trifluoromethyl)-2-cyano group-1,4-dihydro-6-picoline-3-methyl-formiate-5-isopropyl formate (0.46g, 1mmoles), piece acid (0.08g, 1.15mmoles) and 0.16 the gram sodium acetate be dissolved in the 10ml acetate, after at room temperature stirring 1.5 hours, pour in water/dichloromethane mixture.Then organic matter layer is told,, used dried over sodium sulfate then, again solvent evaporation is fallen with sodium hydrogen carbonate solution and water washing.Be added dropwise to sherwood oil (60～80 °) and just obtain 0.31 gram 4-(3-chloro-6-fluoro-2-trifluoromethyl)-1,4-dihydro-2-fat methyl-6-picoline-3-methyl-formiate-5-isopropyl formate, 155～159 ° of fusing points
Resulting fat (0.3g, 0.65mmoles) (0.11g 0.67mmoles) is dissolved in the 5ml anhydrous tetrahydro furan with N-TFA base imidazoles; be heated to reflux temperature; keep after 1.5 hours solvent evaporation being fallen, and after the dropping ether leaches solids in residue, the filtrate evaporate to dryness.Recrystallization just obtains 0.095 gram example name compound, 212～214 ° of fusing points in ethyl acetate/petroleum ether (60～80 °)
Example 74:
4-(3-cyano group-2-thienyl)-and 2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-isopropyl formate.
The product of use-case 81 is by the method preparation of example 73, fusing point: 145～146 ° of (acetone/sherwood oils (60～80 °)
Example 75:
4-(3-chloro-6-fluoro-2-trifluoromethyl)-and 2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid-6-(5-phenyl-3-pyrazoles oxygen) just own ester.
2; 4-dihydro-5-phenyl-3-hydrogen-pyrazoles-3-ketone (0.4g; 2.5mmoles) under agitation add and contain sodium hydroxide solution (50% of 0.12g; 2.5mmoles) the 8ml methyl-sulphoxide in; add 4-(3-chloro-6-fluoro-2-trifluoromethyl after 45 minutes)-2-methyl fluoride-1; 4-dihydro-6-picoline-3-methyl-formiate-5-formic acid-6-(((4-aminomethyl phenyl) just own ester (1.7g oxygen alkylsulfonyl)); 2.5mmoles) methyl-sulphoxide (5ml) solution; after this reaction soln stirs following 7 hours; pour into and also use dichloromethane extraction in the rare acid; dried over mgso is used in organic extract liquid water and piece water washing.Then solvent evaporation is fallen, behind chromatogram (silicon is carrier, and tetrahydrofuran (THF)/normal hexane mixture is an eluant) purifying, crystallization just obtains 0.98 gram example name compound, 141～142 ° of fusing points in 2-propyl alcohol/normal hexane.
Example 76:
4-(3-chloro-6-fluoro-2-trifluoromethyl)-and 2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid-6-(6-methyl-2-phenyl-4-pyrimidyl) oxygen) piece acid half etherate of just own ester.
Sodium hydride (50% of 0.13g; 2.5mmoles) under agitation; be added to 6-methyl-2-phenyl-4-ancymidol (0.47g; 2.5mmoles) methyl-sulphoxide (9ml) solution in; after one hour; add 4-(3-chloro-6-fluoro-2-trifluoromethyl)-2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid-6-(((4-aminomethyl phenyl) alkylsulfonyl) oxygen) just own ester (1.7g, methyl-sulphoxide 2.5mmoles) (2ml) solution.Stir this solution after 16 hours, add entry, and use ethyl acetate extraction.This organic extract liquid water (* 2) and piece water washing.Use dried over sodium sulfate, then solvent evaporation is fallen, behind chromatogram (silicon is carrier, and ethyl acetate/petroleum ether (60～80 °) mixture is an eluant) purifying, obtain the free alkali of 0.6g example name compound.In 2-propyl alcohol/ethyl acetate, form piece acid piece, boil off solvent then, ether is added drop-wise in the residue, just obtain 0.52g example name compound.Fusing point: 113～115 °
Example 77:
4-(3,6-two fluoro-2-trifluoromethyls)-2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid-6-(5-phenyl-3-pyrazoles oxygen) just own ester.
(7.23g, (50% of 0.217g is in inferior wind (60～) solution of diformazan 4.5mmoles) 4.5mmoles) under agitation to be added to sodium hydride 2.4-dihydro-5-phenyl-3 hydrogen-pyrazoles-3-ketone.After 1 hour; add 4-(3.6-two fluoro-2-trifluoromethyls)-2-methyl fluoride-1; 4-two chloro-6-picolines-3-methyl-formiate-5-formic acid-6-(((4-aminomethyl phenyl) oxygen alkylsulfonyl)) (3.0g is in methyl-sulphoxide 4.5mmoles) (5ml) solvent for normal hexane.Stir this solution after 15 hours, reaction mixture is poured in the rare acid, and with ethyl acetate (* 3) extraction, water and piece water washing organic extract liquid are used dried over mgso, then solvent evaporation is fallen, with chromatogram (silicon is carrier) purifying, use ethyl acetate/normal hexane and dichloromethane/ethyl acetate mixture elution twice respectively, crystallization in ethyl acetate/normal hexane, just obtain example name compound, fusing point: 126～128 °
Example 78
4-(3-chloro-6-fluoro-2-trifluoromethyl)-and 2-methyl fluoride-1.4-dihydro-6-picoline-3-methyl-formiate-5-formic acid-6-(5-methyl-3-pyrazoles oxygen) just own ester.
The method preparation of use-case 75～77.128～130 ° of fusing points (ethyl acetate/hexanaphthene)
Example 79
4-(3,6-two fluoro-2-trifluoromethyls)-2-formyl radical-1,4-dihydro-6-picoline-3-methyl-formiate-5-first Iso Butyl Acetate.
4,4-dimethoxy-3-ketobutyric acid methyl esters (6.5g, 3.7mmoles) and ammonium acetate (2.84g 3.7mmoles) is added in (60ml) butyl alcohol-tert, is heated to 55 °.Keep just obtaining 3-amino-4 after 6 hours, 4-dimethoxy-3-M Cr adds 3, and (7.75g is 3.7mmoles) with 3-ketobutyric acid isopropyl ester (5.7g, butyl alcohol-tert 3.7mmoles) (60ml) solution for 6-two fluoro-2-trifluoromethylated benzaldehydes.Be heated to 50 °, keep after 4 days, solvent evaporation is fallen, residue HPLC purifying, eluant is ethyl acetate/normal hexane mixture, thereby obtain buttery 4-(3,6-two fluoro-2-trifluoromethyls)-2-dimethoxy-methyl-1.4-dihydro-6-picoline-3-methyl-formiate-5-isopropyl formate.
This oily matter (3.8g) is dissolved in the formic acid (20ml), stirs under the room temperature after 3 hours, add ethyl acetate (100ml).With this solution difference water, dried over mgso is used in sodium hydrogen carbonate solution and water washing, solvent evaporation is fallen again then.(silicon is carrier, and ethyl acetate/normal hexane mixture is an eluant with chromatogram.) behind the purifying, be added dropwise to normal hexane again, just obtain example name aldehyde (1.2g) fusing point.127～128°
Example 80
4-(3-chloro-6-fluoro-2-trifluoromethyl)-2-formyl radical-1,4-dihydro-6-picoline-3-methyl-formiate-5-isopropyl formate.
The preparation of the method for use-case 79, product such as example 70 identical.
Example 81
2-methyl fluoride-4-(3-formyl radical-2-thienyl)-1,4-dihydro-6-picoline-3-methyl-formiate-5-propyl formate.
With 4-(3-(1,3-dioxolane-2-yl)-the 2-thienyl)-2-methyl fluoride-1,4-dihydro-6-picoline-3-formic acid formic acid-5-isopropyl formate (1.4g) at room temperature mixes with tetrahydrofuran (THF) (25ml) and rare acid (5ml), stir after 15 minutes, pour in water/ether mixture, ether extraction liquid sodium hydrogen carbonate solution and water washing, use dried over mgso, solvent evaporated, residue crystallization in ethyl acetate/petroleum ether (60～80 °), just obtain example name aldehyde (1.1g), fusing point: 135～137 °.
Example 82
The 2-((2-amino ethoxy) methyl)-4-(3-chloro-6-fluoro-2-trifluoromethyl)-6-methyl fluoride-1, the toxilic acid piece hydrate of 4-phenodiazine-Nicotinicum Acidum ethyl ester-5-methyl-formiate.
4-(3-chloro-6-fluoro-2-trifluoromethyl)-2-((2-(1,3-dihydro-1,3-dioxo-2 hydrogen-isoindole-2-yl) methyl oxyethyl group))-6-methyl fluoride-1,4-dihydropyridine-3-ethyl formate-5-methyl-formiate (2.65g, 4mmoles) and hydrazine hydrate (0.58ml 12mmoles) is dissolved in the ethanol, be heated to reflux temperature, after one hour, remove and desolvate, (5 * 50ml) extract residue with ether.Ether extraction liquid washes with water, after dried over mgso, solvent evaporation is fallen.Through chromatogram (silicon is carrier, and methylene dichloride/alcohol mixture is an eluant) purifying, just obtain the free alkali of 1.5g example name compound.Then, (0.34g in ethanol 3mmoles) (10ml) solution, again with the dilution of 40ml ether, just obtains 1.6g example name compound, fusing point: 161 °～163 ° it to be added to toxilic acid.
Example 83
The amino butyl of 2-(4-)-4-(3-chloro-6-fluoro-2-trifluoromethyl)-6-methyl fluoride-1,4-dihydropyridine-3-methyl-formiate-5-methyl-formiate toxilic acid piece.
With 4-(3-chloro-6-fluoro-2-trifluoromethyl)-2-(4-(1,3-dihydro-1,3-dioxo-dihydro-isoindole-2-yl) butyl)-6-methyl fluoride-1,4-dihydropyridine-3-ethyl formate-5-methyl-formiate.(2.9g, 4.53mmoles) and hydrazine hydrate (0.67ml 13.6mmoles) is dissolved in the 50ml ethanol, is heated to reflux temperature.After 3 hours, chilled solution is filtered, and ethanol evaporation is fallen residue 100ml extracted with diethyl ether.Ether extraction liquid washes with water, after the dried over mgso, and evaporate to dryness.Residue is dissolved in the ethanol, and (0.525g 4.5mmoles) adds ether again, just obtains solid metal block, and solid metal block is recrystallization in ethanol/ether mixture, just obtains example name compound (1.8g) to add toxilic acid.Fusing point: 161～162 °.
Example 84
The amino butyl of 2-(4-)-4-(3-chloro-6-fluoro-2-trifluoromethyl)-6-methyl fluoride-1,4-dihydropyridine-3-isopropyl formate-5-methyl-formiate toxilic acid piece.
Select of the method preparation of suitable reactant for use by example 82～83.Fusing point: 167～168 ° (ether)
Example 85
4-(3-amino-6-fluoro-2-trifluoromethyl)-and 2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-isopropyl formate.
With 2-methyl fluoride-4-(6-fluoro-3-((2; 2; the 2-trifluoroacetyl group) amino)-and the 2-trifluoromethyl)-1, (1.0g 1.8mmoles) is dissolved in the 30ml tetrahydrofuran (THF) with the 0.5g sodium borohydride 4-dihydro-6-picoline-3-methyl-formiate-5-isopropyl formate.Stir after four days under the room temperature, solvent evaporation is fallen, residue is dissolved in ethyl acetate/water mixture.Organic matter layer is told, after dried over mgso, boiled off solvent.Residue is dissolved in the 30ml tetrahydrofuran (THF), and adds the 0.2g sodium borohydride, and stirring is spent the night.After above-mentioned steps is finished, promptly use chromatogram purification (silicon is made carrier, and toluene/ethyl acetate is made eluant), just obtain 0.23g example name compound.197～198 ° of fusing points (2-propyl alcohol/sherwood oil (60～80 °)).
Example 86
4-(3-chloro-6-fluoro-2-trifluoromethyl)-and 2-methyl fluoride-1,4-dihydro-6-methyl-3-methoxycarbonyl-5-pyridine carboxylic acid-2-cyano group ethyl ester.
3-chloro-6-fluoro-2-trifluoromethylated benzaldehyde (68g, 0.3moles), 4-fluoro-3-ketobutyric acid methyl esters (40.2g, 0.3moles) be dissolved in the anhydrous butyl alcohol-tert of 60ml, be heated to 55 ℃ under the nitrogen, after 8 days, with this mixture cooling, product leaches, and crystallization makes and obtains example name compound 34g in the 2-propyl alcohol.Fusing point: 167～168 °.
Example 87
4-(3-chloro-6-fluoro-2-trifluoromethyl)-and 6-methyl fluoride-1,4-dihydro-5-methoxycarbonyl-2-methyl-3-pyridine carboxylic acid.
120ml is dissolved with sodium hydroxide (3.75g, water 0.094moles), agitation condition add 60ml down and be dissolved with 4-(3-chloro-6-fluoro-2-trifluoromethyl)-2-fluorine formaldehyde-1,4-dihydro-6-methyl-3-methoxycarbonyl-5-pyridine carboxylic acid-2-cyano group ethyl ester.(17.6g, glyme 0.037moles) stirred after 16 hours, this solution poured in rare acid of 350ml, and the solids elimination, water and methanol wash, drying just obtains the acid of 14.0g example name, fusing point: 209 °～210 ° under the vacuum.
Example 88
4-(3-cyano group-6-fluoro-2-trifluoromethyl)-and 6-methyl fluoride-1,4-dihydro-5-methoxycarbonyl-2-methyl-3-pyridine carboxylic acid.
30ml is dissolved with sodium hydroxide (1.42g, 35mmoles) be added to 30ml under the aqueous solution agitation condition and be dissolved with 4-(3-cyano group-6-fluoro-2-trifluoromethyl)-2-methyl fluoride-1,4-dihydro-6-methyl-3-methoxycarbonyl-5-pyridine carboxylic acid-2-cyano group ethyl ester (8.34g, in glyme 17mmoles), stir after 3 hours, reaction mixture is poured in the rare acid, the solid elimination, wash with water, vacuum-drying just obtains the sour 5.3g of example name.M +416。
Example 89
4-(3,6-two fluoro-2-trifluoromethyls)-2-methyl fluoride-1,4-dihydro-6-methyl-3-methoxycarbonyl-5-pyridine carboxylic acid-2-cyano group ethyl ester.
3,6-two fluoro-2-trifluoromethylated benzaldehyde (21g, 0.1moles), 4-fluoro-3-ketobutyric acid methyl esters (13.4g, 0.1moles) and 3-amino-2-butylene acid-2-cyano group ethyl ester (15.4g, 0.1moles) be dissolved in the anhydrous butyl alcohol-tert of 100ml, be heated to 60 ° under the nitrogen, after four days, solvent evaporation is fallen, residue is dissolved in the 250ml methylene dichloride and adds the 5ml trifluoacetic anhydride, adds 20ml methyl alcohol after 15 minutes, then solvent evaporation is fallen, use the HPCL purifying, eluant is ethyl acetate/petroleum ether (60～80 a °) mixture, just obtains 12.4g example name ester, fusing point: 143～145 ° of (2-propyl alcohol/sherwood oils (60～80 °).
Example 90
4-(3,6-two fluoro-2-trifluoromethyls)-6-methyl fluoride-1,4-dihydro-5-methoxycarbonyl-2-methyl-3-pyridine carboxylic acid.
70ml is dissolved with sodium hydroxide (3.2g, 80mmoles) water and 70ml are dissolved with 4-(3,6-two fluoro-2-trifluoromethyl-2-methyl fluorides-1, (12.4g, glyceryl alcohol diether 27mmoles) mixes 4-dihydro-6-methyl-3-methoxycarbonyl-5-pyridine carboxylic acid-2-cyano group ethyl ester.Stir after 16 hours, this solution is added in the 600ml water, and with extracted with diethyl ether once.Aqueous phase layer is with rare acidifying, and uses the ethyl acetate extraction throw out, and oil reservoir is told.With after the dried over mgso solvent being steamed, just obtain the 10.5g example name and description of a thing.Fusing point: 187 °.
Example 91
4-(3-chloro-6-fluoro-2-trifluoromethyl)-and 2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid-(((4-aminomethyl phenyl) alkylsulfonyl) oxygen) just own ester.
With (4.88g, 23.5mmoles) phosphorus pentachloride, be added to 350ml under the agitation condition and be suspended with 4-(3-chloro-6-fluoro-2-trifluoromethyl-6-methyl fluoride-1,4-dihydro-5-methoxycarbonyl-2-methyl-3-pyridine carboxylic acid (10g, 23.5mmoles) methylene dichloride in, after one hour, slowly add 100ml again and contain the just own ester of 4-toluene sulfonic acide-6-hydroxyl (5.64g, methylene dichloride 23.5mmoles).After 16 hours, under vigorous stirring, adding 5% aqueous sodium carbonate, is 7～8 until the pH of aqueous phase layer value.Organic layer is told, used the piece water washing, use dried over mgso, then solvent is steamed, use the HPLC purifying again, (silicon is carrier, and ethyl acetate/petroleum ether (60～80 °) mixture is an eluant) just obtains 11.8g oily example name compound.
Nuclear magnetic resonance spectrum: δ (CDcl 3) 2.32(S, 3H), 2.45(S, 3H), 3.56(S, 3H) and 5.93(f, 1H).
Example 92
4-(3,6-two fluoro-2-trifluoromethyls)-2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid-6-(((4-aminomethyl phenyl) alkylsulfonyl) oxygen) just own ester.
3; 6-two fluoro-2-trifluoromethyl formaldehyde (3.32g, 16mmoles), 4-fluoro-3-ketobutyric acid methyl esters (2.3g; 17mmoles) with 3-amino-2-butenoic acid-6-(((4-aminomethyl phenyl) alkylsulfonyl) oxygen) just own ester (5.2g; 16mmoles) be dissolved in the 80ml butyl alcohol-tert, be heated to 55 °, after the week; solvent is steamed; residue is dissolved in the 80ml methylene dichloride, and in room temperature, adds the 0.75ml trifluoacetic anhydride under the stirring condition.Adding 10ml methyl alcohol after 10 minutes falls solvent evaporation then.Silicon is carrier, and ethyl acetate/petroleum ether (60～80 °) mixture is an eluant, just obtains 5.8g oily example name compound with the HPLC purifying.
Nuclear magnetic resonance spectrum: δ (CDCl 3) 2.32(S, 3H), 2.44(S, 3H), 3.56(S, 3H), 5.83(f, 1H).
Example 93
4-(3-chloro-6-fluoro-2-trifluoromethyl-2-((2-(1,3-dihydro-1,3-dioxo-2 hydrogen-isoindole-2-yl) oxyethyl group) methyl)-the 6-(methyl fluoride)-1,4-dihydropyridine-3-ethyl formate-5-methyl-formiate
4-(2-(1,3-dihydro-1,3-dioxo-2 hydrogen-isoindole-2-yl)-oxyethyl group-ethyl 3-oxobutanoate (14.7g, 46mmoles) and ammonium acetate (3.9,51mmoles) be dissolved in the 100ml butyl alcohol-tert, be heated to 60 °, after 2 hours, add 3-chloro-6-fluoro-2-three fluoro-2-trifluoromethylated benzaldehyde (10.4g, 46mmoles) with 4-fluoro-3-ketobutyric acid methyl esters (6.2g, 46mmoles), keep 60 ° of temperature, after four days, solvent evaporation is fallen, residue chromatogram purification, carrier are silicon, and ethyl acetate/petroleum ether (60～80 °) mixture is that eluant just obtains 2.6g example name compound.Fusing point: 159～160 °
M +, 642/4; Nuclear magnetic resonance spectrum: δ (CDCl 3) 3.63(S, 3H), 6.08(f, 1H), 8.2(d, 1H).
Example 94
4-(3-chloro-6-fluoro-2-trifluoromethyl)-and 2-(4-(1,3-dihydro-1,3-dioxo-2 hydrogen-isoindole-2-yl) butyl)-6-methyl fluoride-1,4-dihydropyridine-3-ethyl formate-5-methyl-formiate
With of the method preparation of suitable reactant by example 93.Fusing point: 170～171 °
M +, 640/2; Nuclear magnetic resonance spectrum δ (CDCl 3) 3.55(S, 3H), 5.95(f, 1H), 7.15(d, 1H).
Example 95
4-(3-chloro-6-fluoro-2-trifluoromethyl)-and 2-(4-(1,3-dihydro-1,3-dioxo-2 hydrogen-isoindole-2-yl) butyl)-6-methyl fluoride-1,4-dihydropyridine-3-methyl-formiate-5-isopropyl formate
Select suitable reactant for use, the method preparation of use-case 93,
Nuclear magnetic resonance spectrum: δ (CDCl 3) 3.57(S, 3H), 6.1(f, H), 7.05(d, H)
The fusing point of this thing: 142～143 °
Example 96
The 2-((2-amino ethoxy) methyl)-and 4-(3-chloro-6-fluoro-2-trifluoromethyl)-1,4-dihydro-6-picoline-3-ethyl formate-5-methyl-formiate maleate
The 2-((2-amino ethoxy) methyl isophthalic acid, 4-(3-chloro-6-fluoro-2-trifluoromethyl)-1, and 4-dihydro-6-methyl fluoride Nicotinicum Acidum ethyl ester-5-methyl-formiate (0.53g, 1.01mmoles), under 1 normal atmosphere, contain 10%Pd/C(0.4g at 20ml) ethanol in carry out hydrogenation.After three hours, with the catalyzer elimination.Solvent evaporation is fallen, and residue is dissolved in ethyl acetate/saturated sodium bicarbonate mixture, and organic matter layer is told, and after being dried with sal epsom, solvent evaporation is fallen.Thereafter, use chromatogram purification, carrier is a silicon, and eluant is a methylene dichloride, and ethanol and triethylamine mixture form piece with toxilic acid then.Just can obtain the toxilic acid piece of example name compound.Fusing point: 182～183 °
Example 97
4-(3-chloro-6-fluoro-2-trifluoromethyl)-and 2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid-(6-(5-phenyl-3-pyrazolyl oxygen) n-hexyl) ester
Fusing point: 132～134 ° (hexanaphthene/dichloromethane/ethyl acetate).
Example 98
2-(4-((5-amino-1 hydrogen-1,2,4-triazole-3-yl) amino) butyl)-4-(3-chloro-6-fluoro-2-trifluoromethyl)-6-methyl fluoride-1,4-dihydropyridine-3-ethyl formate-5-methyl-formiate
The method preparation of use-case 100.Fusing point: 108～110 ° (sherwood oil (60～80 °)/ether).
Example 99
4-(3-chloro-6-fluoro-2-trifluoromethyl)-and 2-methyl fluoride-1,4-dihydro-2-(4-(2,4,5-trimethylammonium-1 hydrogen-imidazoles-1-yl) butyl-pyridinium-3-methyl-formiate-5-ethyl formate
Method preparation with 101 examples.Fusing point: 169～171 ° (sherwood oil (60～80 °)/acetone)
Example 100
2-((2-((5-amino-1 hydrogen-1,2,4-three imidazo-3-yls) amino) oxyethyl group) methyl)-4-(3-chloro-6-fluoro-2-trifluoromethyl)-6-methyl fluoride-1,4-dihydropyridine-3-ethyl formate-5-methyl-formiate
N-cyano group imidazoles dithio formic acid dimethyl ester (0.175g, 1.2mmoles) and the 2-((2-amino ethoxy) methyl)-4-(3-chloro-6-fluoro-2-trifluoromethyl)-6-fluorine base-1,4-dihydropyridine-3-ethyl formate-5-methyl-formiate (0.41g, 1mmoles) be dissolved in the 5ml2-propyl alcohol, stir after 4 hours under the room temperature, adding ether (10ml) continues to stir 1.5 hours, can obtain 0.5g4-(3-chloro-6-fluoro-2-trifluoromethyl-2-((2-(((cyanoimino after the filtration) methylthio group) methyl) amino) oxyethyl group) methyl)-6-methyl fluoride-1,4-dihydro-6-picoline-3-ethyl formate-5-methyl-formiate
The fusing point of this thing is 177～180 ° (decomposition)
Above-mentioned solid (0.5g) and 0.21ml hydrazine hydrate are added in the 5ml ethanol, are heated to reflux temperature after 3 hours, solvent evaporation is fallen, carry out chromatogram purification, just can obtain 0.27g example name compound with methylene chloride/methanol mixture.
Fusing point: 96～98 °.
Example 101
4-(3-chloro-6-fluoro-2-trifluoromethyl)-and 2-methyl fluoride-1,4-dihydro-6-((2-(2,4,5-trimethylammonium-1 hydrogen-imidazoles-1-yl) oxyethyl group) methyl) Nicotinicum Acidum methyl esters-5-ethyl formate
The 2-((2-amino ethoxy) methyl)-4-(3-chloro-6-fluoro-2-trifluoromethyl)-6-methyl fluoride-1, the 4-dihydro-
(0.51g, 1mmoles) and hexahydro--2,4,6-trimethylammonium-1,3,5-triazine trihydrate (0.365g, 2mmoles) be dissolved in the 5ml methyl alcohol, 0 ° of temperature stirs after one hour, add 2ml and contain 2, the 3-dimethyl diketone (0.35g, methyl alcohol 4mmoles), and keep this reaction mixture after reacting 16 hours under 0 °, add 5ml ammonia (d0.88) again and keep this mixture under 0 °, reacted 24 hours.Crystallisate is leached, and in ethanol/water mixture recrystallization, just obtain 0.49g example name product.Fusing point: 76～78.
Example 102
4-(3-ammonia-6-fluoro-2-trifluoromethyl)-and the 2-((2-(dimethylamino) oxyethyl group) methyl)-6-methyl fluoride-1,4-dihydropyridine-3-ethyl formate-5-methyl-formiate maleate
The 4-((2-(dimethylamino) oxyethyl group)-ethyl 3-oxobutanoate (6.47g, 30mmoles), ammonium acetate (2.4g, 31mmoles) and the mixture heating up to 60 of 150ml butyl alcohol-tert ° keep after 2 hours, add 4-fluoro-3-ketobutyric acid methyl esters (4.03g, 30mmoles) with 4-chloro-6-fluoro-2-trifluoromethylated benzaldehyde (6.8g, 30mmoles), 60 ° are continued down to keep after 3 days solvent evaporated, and residue is dissolved in the 100ml methylene dichloride, and add the 2ml trifluoacetic anhydride.Boil off solvent after 10 minutes, residue chromatogram purification, carrier are silicon, and eluant is tetrahydrofuran (THF)/sherwood oil (60～80 °)/triethylamine mixture.After generating the toxilic acid piece, recrystallization in ethanol just obtains 1.95g example name compound, fusing point: 123～125 °
Example 103
4-(3-cyano group-6-fluoro-2-trifluoromethyl)-and 2-methyl fluoride-1,4-dihydro-1,6-lutidine-3-methyl-formiate-5-formic acid ring butyl ester
Powdered potassium hydroxide (0.336g, 6mmoles) under agitation be added to 4-(3-cyano group-6-fluoro-2-trifluoromethyl)-2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid ring butyl ester (0.7g, 15mmoles) and methyl iodide (0.43g, dimethyl sulfone 3mmoles) (14ml) solution, after 15 minutes, this reaction mixture is poured in the water, and used the ethyl acetate extraction product.The piece water washing of this organic extract after the dried over mgso, boils off solvent.With silicon is carrier, and ethyl acetate/petroleum ether (60～68 °) is the chromatogram purification of eluant, just can obtain 0.35g, example name compound.Fusing point: 110～112 °.
Example 104
2-((2-(1,3-dihydro-1,3-dioxo-2 hydrogen-isoindole-2-yl) oxyethyl group) methyl)-6-methyl fluoride-1,4-dihydro-4-(2,3,6-trifluorophenyl pyridine)-5-methyl-formiate-3-isopropyl formate.
The method preparation of use-case 93.Fusing point: 141～143 ° (ethanol/ether).
Example 105
The 2-((2-amino ethoxy) methyl)-and 6-methyl fluoride-1,4-dihydro-4-(2,3,6-trifluorophenyl pyridine)-3-5-methyl-formiate-3-isopropyl formate.
Use-case 82 and the preparation of 83 method
Nuclear magnetic resonance spectrum: δ (CDCl 3) 5.45(S, H), 3.60(S, 3H).
Example 106
4-(3-chloro-6-fluoro-2-difluoromethyl phenyl)-and the 2-((2-(4((4-chloro-phenyl-) methyl)-the 1-piperazine) oxyethyl group) methyl)-6-methyl fluoride-1, the two oxalic acid pieces of 4-dihydropyridine-5-methyl-formiate-3-ethyl formate.
The method preparation of use-case 7, and change double oxalate (methyl alcohol) into.
Nuclear magnetic resonance spectrum: δ (CDCl 3) 5.89(f, 1H), 5.55(m, 2H)
Example 107
4-(3 chloro-6-fluoro-2-trifluoromethyl)-1,4-dihydro-2-methyl-6-((2-(1-piperazinyl) oxyethyl group) methyl) Nicotinicum Acidum methyl esters-5-ethyl formate
4-(3-chloro-6-fluoro-2-trifluoromethyl)-1,4 dihydros-2-((2-(4-((4-chloro-phenyl-) methyl)-and the 1-piperazinyl) oxyethyl group) methyl)-6-methyl fluoride pyridine-5-methyl-formiate-3-ethyl formate (3.5g, 4mmoles) be dissolved in 500ml methyl alcohol and the 1ml acetate, and adding 5%Pd/C, this mixture is at 45 pounds/English inch 2Pressure under, carry out hydrogenation after 16 hours, catalyzer is leached, boil off solvent.Residue is dissolved in methylene dichloride/sodium hydrogen carbonate solution, and organic matter layer is told, and uses dried over mgso, then solvent evaporation is fallen, and just obtains 1.4g example name compound.
Nuclear magnetic resonance spectrum: δ (CDCl 3) 5.99(f, 1H), 4.70(f, 2H).
Example 108
4-(3-chloro-6-fluoro-2-trifluoromethyl)-1,4-dihydro-2-methyl-6-((2-4((methylamino) carbonyl)-the 1-piperazinyl) oxyethyl group) methyl) Nicotinicum Acidum methyl esters-5-ethyl formate.
4-(3-chloro-6-fluoro-2-trifluoromethyl)-1,4-dihydro-2-methyl-6-((2-(1-piperazinyl) Nicotinicum Acidum methyl esters-5-ethyl formate (0.05g methyl oxyethyl group)), 0.09mmoles) and methyl isocyanate (0.008ml, 0.9mmoles) be dissolved in and stir after 1 hour in the 1ml chloroform, boil off solvent, residue just obtains 0.025g example name compound through chromatogram purification (silicon is carrier, and methylene chloride/methanol mixture is an eluant).
Nuclear magnetic resonance spectrum: δ (CDCl 3) 5.97(f, 1H), 2.85(d, 3H), 2H(S, 3H)
Example 109
4-(3-chloro-6-fluoro-2-trifluoromethyl)-and 2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-ethyl formate
Method preparation by example 2 and example 4.Fusing point: 159～61 ° (acetone/sherwood oil (60～80 °))
Example 110
4-(3-chloro-6-fluoro-2-trifluoromethyl)-and 2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid ring butyl ester.
Method preparation by example 2 and example 4.135～7 ° of fusing points, (sherwood oil (60～80 °))
Example 111
4-(3-chloro-6-fluoro-2-trifluoromethyl)-and 2-fluorophenyl-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid-2-methyl propyl ester
Method preparation by example 2 and example 4.Fusing point: 158～9 ° (2-propyl alcohol)
Example 112
4-(3-chloro-6-fluoro-2-trifluoromethyl)-and 2-methyl fluoride-1,4-dihydro-6-picoline-3-isopropyl formate-5-methyl-formiate
Method preparation by example 2 and example 4.135～7 ° of fusing points, (sherwood oil (60～80 °))
Example 113
4-(3-chloro-6-fluoro-2-trifluoromethyl)-and 2-methyl fluoride-1,4-dihydro-6-picoline-3-ethyl formate-5-methyl-formiate
Method preparation by example 2 and example 4.Fusing point: 148～50 ° (2-propyl alcohol)
Example 114
The basic phenyl of 4-(3-chloro-6-fluoro-2-trifluoro)-and 2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid-(3-oxa-cyclobutyl) ester
Method preparation by example 6.Fusing point: 158.5～160 ° (acetone/sherwood oil (60～80 °))
Example 115
4-(3-chloro-6-fluoro-2-trifluoromethyl)-and 2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid (tetrahydrochysene-4 hydrogen-pyrans-4-yl) ester
Method preparation by example 2 and example 4.88～90 ° of fusing points, (acetone/sherwood oil (60～80 °))
Example 116
4-(3-chloro-6-fluoro-2-trifluoromethyl)-and 2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid-(2,2, the 2-trifluoro ethyl ester)
Method preparation by example 6.Fusing point: 164～6 ° (acetone/sherwood oil (60～80 °))
Example 117
4-(3-chloro-6-fluoro-2-trifluoromethyl)-and 2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid-(2,3-dihydro-2-saves base) ester
Method preparation by example 6.Fusing point: 169～71 ° (acetone/sherwood oil (60～80 °))
Example 118
4-(3-chloro-6-fluoro-2-trifluoromethyl)-and 2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid-(2-methyl isophthalic acid-(methylethyl) propyl group) ester
Dicyclohexyl carbodiimide (0.48g, 2.3mmoles) under the agitation condition, be added to 4-(3-chloro-6-fluoro-2-trifluoromethyl)-6-methyl fluoride-1,4-dihydro-5-methoxycarbonyl-2-methyl-3-pyridine carboxylic acid (1.0g, 23mmoles) with 2, (2.73g is in methylene dichloride 23mmoles) (10ml) solution for 4-dimethyl-3-amylalcohol.After 20 hours, reaction mixture is filtered, boil off solvent, add the 20ml ether then.After 1 hour this solution is filtered, boil off ether.Residue just obtains 0.135g example name compound with chromatogram purification (silicon is carrier, and ethyl acetate/normal hexane mixture is an eluant).Fusing point: 179～81 ° (2-propyl alcohol/hexanaphthene).
Example 119
4-(3-chloro-6-fluoro-2-trifluoromethyl)-and 2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid-2,2-dimethyl propyl ester.
Method preparation by example 7.Fusing point: 169～71 ° (sherwood oil (60～80 °))
Example 120
4-(3-chloro-6-fluoro-2-trifluoromethyl)-and 2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid-1,1-dimethyl ethyl ester.
Method preparation by example 53～55.121～2 ° of fusing points (normal hexane)
Example 121
4-(3-chloro-6-fluoro-2-trifluoromethyl)-and 2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid-2-fluoro-1-methyl fluoride ethyl ester.
Method preparation by example 118.Fusing point: 124～5 ° (hexanaphthene)
Example 122
4-(3-chloro-6-fluoro-2-trifluoromethyl)-and 2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid-2,2,2-three fluoro-1-trifluoromethyl ethyl esters.
Method preparation by example 53～55.Fusing point: 102～4 ° (sherwood oil (60～80 °)), M +577/5.Nuclear magnetic resonance spectrum: δ (CDcl 3) 6.00(f, H), 3.59(S, 3H).
Example 123
4-(3-chloro-6-fluoro-2-trifluoromethyl)-and 2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid oxyethyl group methyl esters.
Method preparation by example 124.Fusing point: 154～5 ° (2-propyl alcohol)
Example 124
4-(3-chloro-6-fluoro-2-trifluoromethyl)-and 2-methyl fluoride-1,4-dihydro-6 picolines-3-methyl-formiate-5-formic acid-2-oxo propyl ester.
Sodium hydride (0.057g(content is 50%), 1.2mmoles), under agitation be added to 4-(3-chloro-6-fluoro-2-trifluoromethyl)-6-methyl fluoride-1, (0.5g is in tetrahydrofuran (THF) 1.2mmoles) (20ml) solution for 4-dihydro-5-methoxycarbonyl-2-methyl-3-pyridine carboxylic acid salt.After one hour, (0.088g 1mmoles), behind the placement fortnight, pours this reaction mixture in dilute hydrochloric acid and the ethyl acetate under the room temperature to add 1-chloro-2-acetone.Water layer extracts with ethyl acetate again, organic extract liquid water and salt water washing, MgSO 4Dry.Boil off solvent, with just obtaining 0.3g example name compound behind the chromatogram purification (carrier is a silicon, and eluant is ethyl acetate/normal hexane).Fusing point: 142～3 ° (2-propyl alcohol/normal hexane).
Example 125
4-(3-chloro-6-fluoro-2-trifluoromethyl)-and 2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid-1-ethyl propyl ester.
Method preparation by example 6.Fusing point: 134～7 ° (sherwood oil (60～80 °))
Example 126
4-(3-chloro-6-fluoro-2-trifluoromethyl)-and 2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid-3-cyclopentenes ester.
Method preparation by example 53～55.Fusing point: 169～71 ° (acetone/sherwood oil (60～80 °)).
Example 127
4-(3-chloro-6-fluoro-2-trifluoromethyl)-and 2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid-3-hydroxyl-2-methylol-2-methyl propyl ester.
0.6g 4-(3-chloro-6-fluoro-2-trifluoromethyl)-2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid-(3-methyl-3-oxa-cyclobutyl) methyl esters is dissolved in the 10ml ethyl acetate, and the hydrochloric acid of adding 10ml 2N, place after 16 hours, organic layer is told, used MgSO 4Drying, and boil off solvent, through chromatogram purification (silicon is carrier, and ethyl acetate/petroleum ether (60～80 °) mixture is an eluant) and in methyl alcohol/2-propyl alcohol/sherwood oil (60～80 °) crystallization just obtain 0.28g example name compound.Fusing point: 122～4 °.
Example 128
The basic phenyl of 4-(3-chloro-6-fluoro-2-trifluoro)-and 2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid-cis-octahydro-bridge-2-pentalene ester.
Method preparation by example 53～55.Fusing point: 205 ° (decomposition).
Example 129
4-(3-chloro-6-fluoro-2-trifluoromethyl)-and 2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid-2,2-dimethyl-3-(methyl (benzyl) amino) propyl ester.
Method preparation by example 7.Fusing point: 115 ° (decomposition).M +616/4。Nuclear magnetic resonance spectrum: δ (D 6DMSO) 5.76(f, H).
Example 130
2-difluoromethyl-4-(3,6-two fluoro-2-trifluoromethyls)-1,4-dihydro-6-picoline-3-methyl-formiate-5-isopropyl formate.
Bifluoride diethylin sulphur (0.36g 2.2mmoles) is added to 4-(3 under-20 ° of stirrings, 6-two fluoro-2-trifluoromethyls)-2-formyl radical-1,4-dihydro-6-picoline-3-methyl-formiate-5-isopropyl formate.(0.9g, methylene dichloride 2mmoles) (50ml) solution.Under 20 °, reacted one hour.Reaction after one hour is fallen solvent evaporation under reflux temperature again, and residue just can obtain 0.34g example name compound with chromatogram purification (silicon is carrier, and ethyl acetate/normal hexane mixture is an eluant), the pure fraction that drips normal hexane.Fusing point: 136～137 °.
Example 131
4-(3-chloro-6-fluoro-2-trifluoromethyl)-and 2-difluoromethyl-1,4-dihydro-6-picoline-3-methyl-formiate-5-isopropyl formate.
Method preparation by example 130.Fusing point: 131～132 ° (normal hexane)
Example 132
4-(3-chloro-6-fluoro-2-trifluoromethyl)-and 2-methyl fluoride-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid-3-nitrogen heterocyclic butyl ester.
Method preparation by example 53～55.Fusing point: 176 ° (decomposition), (ethanol/ether).M +480/2; Nuclear magnetic resonance spectrum: δ (D 6DMSO) 9.3(S, 1H), 5.83(f, 1H), 3.6(S, 3H).
Example 133
4-(3-chloro-6-fluoro-2-trifluoromethyl)-and 2-((2-(1,3-dihydro-1,3-dioxo-2 hydrogen-isoindole-2-yl) oxyethyl group) methyl)-6-methyl fluoride-1,4-dihydropyridine-5-methyl-formiate-3-formic acid-2,2,2-trichloro ethyl ester.
Method preparation by example 6.Nuclear magnetic resonance spectrum: δ (CDCl 3), 6.05(f, 1H), 3.56(S, 3H).
Example 134
4-(3-chloro-6-fluoro-2-trifluoromethyl)-and 2-((2-(1,3-dihydro-1,3-dioxo-2 hydrogen-isoindole-2-yl) oxyethyl group) methyl)-6-methyl fluoride-1,4-dihydropyridine-5-methyl-formiate-3-formic acid.
With (0.31g, 4.75mmoles) zinc powder), under agitation condition, join 4-(3-chloro-6-fluoro-2-trifluoromethyl)-2-((2-(1,3-dihydro-1,3-dioxo-2 hydrogen-isoindole-2-yl) oxyethyl group) methyl)-6-methyl fluoride-1,4-dihydropyridine-5-methyl-formiate-3-formic acid-2,2, (0.7g, (0.18ml is 4.75mmoles) and in acetonitrile (10ml) solution for the formic acid that contains 0.95mmoles) for the 2-trichloro ethyl ester.After three days, this reaction mixture is poured in the piece water, the aqueous sulfuric acid with 10% carries out acidifying.Use chloroform extraction then.Organic matter layer is told, and sulphuric acid soln with 10% and piece water washing after the dried over mgso, can obtain example name compound behind the evaporate to dryness.M ++1，615/7。
Example 135
4-(3-chloro-6-fluoro-2-trifluoromethyl)-and 2-((2-(1,3-dihydro-1,3-dioxo-2 hydrogen-isoindole-2-yl) oxyethyl group) methyl)-6-methyl fluoride-1,4-dihydropyridine-3-isopropyl formate-5-methyl-formiate.
Method preparation by example 53～55.M +656/8。
Example 136
The 2-((2-amino ethoxy) methyl)-4-(3-chloro-6-fluoro-2-trifluoromethyl)-6-methyl fluoride-1,4-dihydropyridine-3-isopropyl formate-5-methyl-formiate.
Method preparation by example 82 and 83.(M+1) +527/9; Nuclear magnetic resonance spectrum: δ (CDCl 3) 835(d, H), 60(f, 1H), 3.57(S, 3H).
Example 137
4-(2,6-two fluoro-3-nitrophenyls)-2-((2-(1,3-dihydro-1,3-dioxo-2 hydrogen-isoindole-2-yl) oxyethyl group) methyl)-6-methyl fluoride-1,4-dihydropyridine-3-isopropyl formate-5-methyl-formiate.
Method preparation by example 93.(M+1) +, 618; Nuclear magnetic resonance spectrum: δ (CDcl 3) 5.35(S, 1H), 3.60(S, 3H).
Example 138
The 2-((2-amino ethoxy) methyl)-and 4-(2,6-two fluoro-3-nitrophenyls)-6-methyl fluoride-1,4-dihydropyridine-3-isopropyl formate-5-methyl-formiate.
Method preparation by example 82 and 83.（M+1）488
Example 139
4-(3-chloro-6-fluoro-2-trifluoromethyl)-1,4-dihydro-2-methyl-6-((2-(4-(2-thiazolyl)-the 1-piperazinyl) oxyethyl group) methyl) Nicotinicum Acidum methyl esters-5-ethyl formate.
4-(3-chloro-6-fluoro-2-trifluoromethyl)-1,4-dihydro-2-methyl-6-((2-(1-piperazinyl) oxyethyl group) methyl) Nicotinicum Acidum methyl esters-5-ethyl formate.(0.05g 0.1mmoles) and the mixture heating up to 120 of 2-bromethiazole (0.02ml) °, keeps after two days, just can obtain a 0.02g example compound through chromatogram purification (carrier is a silicon, and eluant is methylene chloride/triethylamine mixture).
(M+1) +647/9; Nuclear magnetic resonance spectrum: (CDcl 3) 5.98(f, 1H), 3.58(S, 3H).
Example 140
4-(3-chloro-6-fluoro-2-trifluoromethyl)-and 2-methyl fluoride-1,4-dihydro-6-(4-methoxyl group-4-oxo butyl) Nicotinicum Acidum methyl esters-5-ethyl formate.
Method preparation by example 6.M +539/41。
Example 141
4-(4-(3-chloro-6-fluoro-2-trifluoromethyl)-and the 3-methyl fluoride-, 4-dihydro-5-methoxycarbonyl-3-ethoxy carbonyl-2-pyridyl) and butyric acid
With 4-(3-chloro-6-fluoro-2-trifluoromethyl)-2-methyl fluoride-1,4-dihydro-6-(4-methoxyl group-4-oxo butyl) Nicotinicum Acidum methyl esters-5-ethyl formate.
Method preparation by example 87,88 and 90.
Nuclear magnetic resonance spectrum: δ (CDCl 3) 6.0(f, 1H), 3.57(S, 3H), 2.5(t, 2H).
Example 142
4-(3-chloro-6-fluoro-2-trifluoromethyl)-and 2-(6-oxyethyl group-4,6-dioxo hexyl)-the 6-methyl fluoride)-1,4-dihydropyridine-3-ethyl formate-5-methyl-formiate.
Be dissolved with 4-(4-(3-chloro-6-fluoro-2-trifluoromethyl at 20ml)-6-methyl fluoride-1,4-dihydro-5-methoxycarbonyl-3-ethoxy carbonyl-2-pyridyl) butyric acid (1.1g, in methylene dichloride 2mmoles), add 0.75g thionyl chloride and a dimethyl formamide.Stir after 16 hours, boil off solvent, the muriate of acid in the middle of just can obtaining.It is dissolved in the 10ml methylene dichloride, and under-20 °, surpasses in 30 minutes time, it is added drop-wise to 2,2-dimethyl-1,3-diox-4, the 6-diketone (0.36g, 2.5mmoles) and pyridine (0.23g, 3mmoles) with the mixing solutions of methylene dichloride (50ml) in.After this reaction mixture at room temperature stirs 3 hours,, use dried over mgso, boil off solvent then with piece acid and piece water washing.Residue is dissolved in the ethanol, is heated to reflux temperature.After 2 hours, boil off solvent.Residue just gets 0.46g example name compound with HPLC purifying (eluant is ethyl acetate/petroleum ether (60～80 a °) mixture).
Nuclear magnetic resonance spectrum: δ (CDCl 3) 6.0(f, 1H) 3.58(S, 3H), 3.47(S, 2H), 2.67(t, 2H).
Example 143
2-(3-(2-amino-6-hydroxyl-4-pyrimidyl) propyl group)-4-(33-chloro-6-fluoro-2-trifluoromethyl)-6-methyl fluoride-1,4-dihydropyridine-3-ethyl formate-5-methyl-formiate (0.46g, 0.77mmoles) piece acid guanidine (0.075g, 0.7gmmoles) and 1,5-diaza-bicyclo (430) ninth of the ten Heavenly Stems-5-alkene (0.14g, 1.1mmoles) be dissolved in the 15ml ethanol, be heated to reflux temperature, keep after 3 hours, boil off solvent, residue just can obtain 0.165g example name compound with chromatogram purification (silicon is carrier, and eluant is a methylene chloride/methanol mixture).（M+1） +591/3。
Example 144
4-(3-chloro-6-fluoro-2-trifluoromethyl)-and 2-methyl fluoride-1,4-dihydro-6-((2-methoxyl group-2-oxo oxyethyl group) methyl) Nicotinicum Acidum methyl esters-5-ethyl formate.
Method preparation by example 6.Nuclear magnetic resonance spectrum: δ (CDcl 3) 6.0(f, 1H), 4.81(f, 2H), 3.58(S, 3H).

Claims (6)

1, a kind of preparation method is used to prepare structure such as compound in structural formula I,
Figure 85106878_IMG2
R wherein 1Be hydrogen atom or C 1～C 6Alkyl,
R 3And R 5Be-(CH 3) x-(CHR 34) yR 35, they can be identical or different,
X is from 0 to 7 integer, comprises 0 and 7,
Y is 0 or 1,
R 34Be hydrogen atom, C 1～C 6Alkyl or the following cycloalkyl of eight carbon atoms (comprising eight carbon atoms),
R 35It can be hydrogen atom; Be to have substituent C 1～C 6Alkyl, substituting group can be: hydrogen atom, C 1～C 6Alkoxyl group or hydroxyl, whether replace that to reach the position of substitution be selectable; Be the quaternary that contains O, N or S (O) n, five yuan or six ring heterocycles, can be substituted with C on the heterocycle 1～C 6Alkyl, whether replace and reach the position of substitution and can select; Be following cycloalkyl or cycloalkenyl groups of eight carbon atoms (comprising eight carbon atoms), wherein cycloalkyl itself can form bridged bond again or by C 1～C 6Alkyl replace, form bridged bond or whether replace to reach and times put and can select, also can and on phenyl ring; Be group-CH=CHR 13, R wherein 13Be the following cycloalkyl of eight carbon atoms (comprising eight carbon atoms); Or C 1～C 6Alkylamino, wherein alkyl can be replaced by phenyl, whether replaces to reach the position of substitution and can select; When X is from 1 to 7 integer when (comprising 1 and 7), R 35Can be cyano group ,-OSO 2R 22Or the group of structure such as structural formula II or III,
R wherein 11And R 12Be C 1～C 6Alkyl or phenyl, it can be identical or different,
R 22And R 6Can be identical or different, they can be CN, CHO or C 1～C 6Alkyl, these alkyl can insert Sauerstoffatom and by halogen atom, hydroxyl ,-COOH or its C 1～C 6Alkyl ester, C 1～C 6The 'beta '-ketoester group, 2-amino-6-hydroxyl miaow pyridine-4-base or-NR 14R 15Group replaces, and insert or whether replace the position that reaches insertion or replace and can select,
R 14And R 15Can be identical or different, they can be hydrogen atom, C 1～C 6Alkyl ,-C (=NCN) S alkyl (C 1～C 6) or the base of structure such as structural formula IV
Figure 85106878_IMG4
Group also can form segment-CR together 16=N-OR 17=CR 18-,-CH 2CH 2--N (R 19) CH 2CH 2-or-CO (neighbour-benzene methylene base) CO-,
R 16, R 17And R 18Be C 1～C 6Alkyl, they can be identical or different,
R 19It can be hydrogen atom; Be C 1～C 6Alkyl, can be replaced by phenyl on the alkyl, whether replace and reach the position of substitution and can select, can be replaced by the plain atom of fontanel on the phenyl, whether replace and reach the position of substitution and can select; Be-COR 20R 21Or contain nitrogen or contain nitrogen and the unsaturated five-ring of sulphur,
R 20And R 21Can be hydrogen atom or C 1～C 6Alkyl, they can be identical or different,
R 4Can have three or four substituent phenyl, or contain the unsaturated quinary heterocyclic radical of one of aerobic, sulphur, nitrogen-atoms; R 4Can have following substituting group; CF 2, XR 22, nitro, halogen atom, CN, C 1～C 6Alkyl, formyl radical, oxalic acid base ,-N (R 22) COR 24,-CONR 25R 26, or amino, can be substituted with benzenesulfonyl or trifluoroacetyl group on amino; R 4Go up and be connected R 4Have a substituting group on the atom adjacent with the atom of the other parts of molecule,
R 22Be phenyl or C 1～C 6Alkyl, can be substituted with halogen atom on the alkyl, whether replace and reach the position of substitution and can select,
X is O or S (O) n,
N is 0,1 or 2,
R 22, R 14, R 25And R 26Can be hydrogen atom or C 1～C 6Alkyl, they can be identical or different,
If i) work as R 1Be hydrogen atom or methyl, R 2Be CH 2F, R 2Be methyl, R 5When being 1-methylethyl or cyclopentyl, R then 4Not 2-trifluoromethyl-3-chloro-6-fluorophenyl,
Ii) work as R 1Be hydrogen atom, R 2Be CH 2F, R 2Be methyl, R 5When being the 1-methylethyl, R then 4Not 2,3-two chloro-6-fluorophenyls,
Iii) work as R 4When being heterocyclic radical, R then 2And R 6Have at least one not to be alkyl or alkoxyalkyl,
Or contain the structural formula I compound of basic nitrogen atom and the additive salt of the acid of can being used as medicine.
Present method comprises:
A) reaction of the compound of structure such as structural formula V, VII, X and XIV.
R 4CHO Ⅴ
R 5OOCCH 2COR 6Ⅶ
R 3OOCCH 2COR 2X
R 1NH 2XIV
Or their partial condensate.
R wherein 1, R 2, R 3, R 4, R 5And R 6Structure such as front define.
B) respective compound (wherein containing group-S (O) m-, m=0,1) of structural formula I compound is carried out selective oxidation reaction, preparation contains the structural formula I compound of group-S (O) m-(m=1,2).
C) respective compound and the fluorizating agent by structural formula I compound reacts the (R in the respective compound 2And R 6One of be or both be respectively-CHO or-CH 2L, L are-OH or good leaving group) preparation R 2And R 6One of be or both are respectively-CHF 2Or-CH 2The structural formula I compound of F.
D) have-the substituent structural formula I of CHO compound by following prepared in reaction;
I) have-CH (OR 27) 2The selective hydrolysis of the respective compound of substituent structural formula I compound.
R wherein 27Be C 1～C 6Alkyl or two R 27Group formation-CH 2CH 2-segment.
Ii) have-CH 2The selective oxidation of the respective compound of the substituent structural formula I of OH compound.
E) pass through R 2And R 6One of be-CH 2The selective hydrolysis of the respective compound of the structural formula I compound of Z (Z is good leaving group), preparation R 2And R 6One of be-CH 2The structural formula I compound of OH.
F) general formula from have-respective compound of the structural formula I compound of CH=NOR group (OR be good leaving group) the reaction of cancellation ROH, preparation has-the structural formula I compound of CN base.
G) reductive cleavage or the hydrolysis reaction of the respective compound by structural formula I compound, wherein R 2And R 5Have at least one not to be hydrogen or R 2And R 6Have at least one to have carboxylic acid ester groups, preparation structural formula I compound, wherein R 3And R 5Have at least one to be hydrogen atom or R 2And R 6Have one at least and have-the COOH base.
H) esterification of the respective compound by structural formula I compound or transesterification reaction (R wherein 3And R 5Have at least one to be hydrogen atom or R 3And R 5One of be not the needed group of purpose product, perhaps R 2And R 6Having one at least is-the COOH yl) preparation structural formula I compound, wherein R 3And R 5Have at least one not to be hydrogen atom, perhaps R 2And R 6Have at least one to have carboxylic acid ester groups or 'beta '-ketoester base.
I) selective reduction of passing through the respective compound of structural formula I compound is reacted, wherein R 2And R 6Have at least one to be-CH 2Y (Y is the group that can be reduced to hydrogen), preparation structural formula I compound, wherein R 2And R 6Have at least one to be methyl.
J) remove blocking group in the respective compound by the structural formula I compound that has protected amino, preparation has-NH 2The structural formula I compound of base.
K) (the R wherein of the respective compound by structural formula I compound 3And R 5Have an alkyl that is replaced by good leavings group at least) respectively with the reaction of structure such as structural formula XI or XII compound or their tautomer or salt, preparation structural formula I compound, wherein R 3And R 5Have at least one to be the substituent alkyl that has structure such as structural formula II or III.
Figure 85106878_IMG5
R wherein 11And R 12Structure such as front define.
L) (the R wherein of the respective compound by structural formula I compound 3And R 5Have an alkyl that is replaced by 3-oxa-cyclobutyl at least, this can be replaced this oxa-cyclobutyl by alkyl again on the 3-position) the selective hydrolysis reaction, preparation structure I compound, wherein R 3And R 5Has one at least by group-CH (R 36) (CH 2OH)-CH 2The alkyl that OH replaces, R 36Be hydrogen atom or alkyl.
M) pass through R 1Be the C of respective compound of the structural formula I compound of hydrogen atom 1～C 6Alkylation, preparation R 1Be C 1～C 6The structural formula I compound of alkyl.
N) (the R wherein of the respective compound by structural formula I compound 14And R 15One of be-C (=NCN) S alkyl (C 1～C 6) and hydrazine reaction, preparation structural formula I compound, wherein R 14And R 15One of be the group of structure such as structural formula IV).
O) (the R wherein of the respective compound by structural formula IV compound 14And R 15All be hydrogen atom) with the reaction of ammonia and alkyl aldehydes and alkane diketone (wherein two Sauerstoffatoms are connected on two adjacent carbon atoms), preparation structural formula I compound, wherein R 14And R 15Formation-CR together 16=N-CR 17=CR 13-chain.
P) (the R wherein of the respective compound by structural formula I compound 10Be hydrogen atom) with alkyl isocyanate or have the pentacyclic reaction of good leaving group accordingly.Preparation structural formula I compound, wherein R 19Be alkylamino-carbonyl or five-ring.
Q) (the R wherein of the respective compound by structural formula I compound 14And R 15Having one at least is hydrogen atom) and N-cyanoimino dithiocarbonic acid dialkyl group (C 1～C 6) the ester reaction, preparation structural formula I compound, wherein R 14And R 15Be group-C (=NCN) S alkyl (C 1～C 6).
R) (the R wherein of the respective compound by structural formula I compound 2And R 6Having one at least often has-the 'beta '-ketoester base) react preparation structural formula I compound, wherein R with guanidine 2And R 6Have at least one to have substituting group 2-amino-6-hydroxyl-pyrimidine-4-base.
S) by taking structural formula I compound optical isomer intermixture apart, prepare the optical isomer of this compound.
And when needs or when essential, otherwise bar structure formula I compound change into its acid of can being used as medicine additive salt or.
2, method according to claim 1, wherein R 4Structure such as structural formula X III
R wherein 7Be trifluoromethyl, benzenethiol base, fluorine atom, Phenylsulfonic acid base, nitro or chlorine atom.
R 8Be itrile group, chlorine atom, fluorine atom, benzenethiol base, thiomethyl alcohol base, phenylsulfonamido, trifluoroacetyl group, trifluoromethyl, methoxyl group, rosickyite alcohol radical, nitro or amino.
R 9Be hydrogen atom, fluorine atom or chlorine atom.
R 10Be hydrogen atom, fluorine atom, methoxyl group or chlorine atom.
3, method according to claim 2, wherein R 1Be hydrogen atom, R 2Be methyl fluoride or methyl, R 3Be methyl, R 5Be 3-thia cyclobutyl, 1-methylethyl, cyclobutyl, 3-thia cyclobutyl-S, S-dioxy, 6-(5-phenyl-3-pyrazolyl oxygen) n-hexyl, cyclopropyl methyl, 6-((6-methyl-2-phenyl-4-pyrimidyl) oxygen) n-hexyl or ethyl, R 6Be methyl or (2-amino ethoxy) methyl, R 4Be the group of 3-nitro-2-thienyl or structure such as structural formula X III, wherein R 7Be trifluoromethyl, R 8Be chlorine atom or itrile group, R 9Be hydrogen atom, R 10It is fluorine atom.
4, method according to claim 1, wherein structural formula I compound is 4-(3-cyano group-6-fluoro-2-(trifluoromethyl) phenyl)-the 2-(methyl fluoride)-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid-3-thia ring butyl ester, be 4-(3-chloro-6-fluoro-2-(trifluoromethyl) phenyl)-the 2-(methyl fluoride)-1,4-dihydro-6-picoline-3-methyl-formiate-5-formic acid (6-((6-methyl-2-phenyl-4-pyrimidyl) oxygen) ester n-hexyl), or its salt that can be used as medicine.
Or 2-((2-amino ethoxy) methyl)-and 4-(3-chloro-6-fluoro-2-(trifluoromethyl) phenyl)-the 6-(methyl fluoride)-1,4-dihydropyridine-3-ethyl formate-5-methyl-formiate, or its salt that can be used as medicine.
5, according to any one described in the claim 1 to 4, the purposes of structural formula I compound is to make the pharmaceutical compositions that is used in the treating cardiovascular disease.
CN 85106878 1984-10-19 1985-09-12 The method for preparing compound Pending CN85106878A (en)

Applications Claiming Priority (17)

Application Number Priority Date Filing Date Title
GB848426563A GB8426563D0 (en) 1984-10-19 1984-10-19 Biologically active esters
GB84/26559 1984-10-19
GB848426562A GB8426562D0 (en) 1984-10-19 1984-10-19 Biologically active esters
GB848426570A GB8426570D0 (en) 1984-10-19 1984-10-19 Biologically active esters
GB84/26560 1984-10-19
GB84/26569 1984-10-19
GB848426569A GB8426569D0 (en) 1984-10-19 1984-10-19 Biologically active esters
GB84/26571 1984-10-19
GB84/26570 1984-10-19
GB84/26562 1984-10-19
GB84/26563 1984-10-19
GB848426571A GB8426571D0 (en) 1984-10-19 1984-10-19 Biologically active esters
GB848426559A GB8426559D0 (en) 1984-10-19 1984-10-19 Biologically active esters
GB848426560A GB8426560D0 (en) 1984-10-19 1984-10-19 Biologically active esters
GB84/30296 1984-11-30
GB848430296A GB8430296D0 (en) 1984-11-30 1984-11-30 Biologically active nitrogen heterocycles
GB85/07163 1985-03-20

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107735428A (en) * 2015-06-17 2018-02-23 三菱瓦斯化学株式会社 Composition for optical material and use its optical material

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107735428A (en) * 2015-06-17 2018-02-23 三菱瓦斯化学株式会社 Composition for optical material and use its optical material

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