CN101668744A - Process for producing 1-substituted-2-pyridone-3-carboxylic acid derivative - Google Patents

Process for producing 1-substituted-2-pyridone-3-carboxylic acid derivative Download PDF

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CN101668744A
CN101668744A CN200780051801A CN200780051801A CN101668744A CN 101668744 A CN101668744 A CN 101668744A CN 200780051801 A CN200780051801 A CN 200780051801A CN 200780051801 A CN200780051801 A CN 200780051801A CN 101668744 A CN101668744 A CN 101668744A
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substituting group
general formula
compound
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alkyl
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海野知宏
森田顺一
筱本敞次
营田良英
井出丰
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Shionogi and Co Ltd
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract

Disclosed are: a process for producing a 1-substituted-2-pyridone-3-carboxylic acid derivative which is an important intermediate for the production of a 2-pyridone-3-carbamoyl derivative that has a cannabinoid receptor agonist activity in a simple manner; and a process for producing the 2-pyridone-3-carbamoyl derivative in a simple manner. Specifically disclosed is a process for producing a compound represented by the general formula (II), which comprises: a step A for hydrolyzing a compound represented by the general formula (I); and a step (B) for adding an alcohol to the hydrolysate of thecompound represented by the general formula (I) produced in the step A to produce a crystal of the compound represented by the general formula (II). (I) wherein R<1> represents an alkyl which may besubstituted by a non-reactive substituent, or the like; R<2> and R<3> independently represent an alkyl or the like, or R<2> and R<3>, together with a carbon atom adjacent to R<2> and R<3>, may form acycloalkene; R<4> represents a hydrogen atom or the like; and R<5> represents an alkyl. (II) wherein R<1>, R<2>, R<3> and R<4> are as defined above.

Description

The preparation method of 1-replacement-2-pyridone-3-carboxylic acid derivatives
Technical field
The present invention relates to have the excellent active 2-pyridone of the cannabinoid receptor agonists-3-carbamoyl derivatives and the preparation method of important intermediate thereof.
Background technology
Record in the patent documentation 1 and 2: 2-pyridone-3-carbamoyl derivatives has excellent cannabinoid receptor agonists activity, and is effective for allergic disease.Record in the patent documentation 3: 2-pyridone-3-carbamoyl derivatives has the 5-HT4 receptor agonist activity.Put down in writing the preparation method of the important intermediate 1-replacement-2-pyridone-3-carboxylic acid derivatives in 2-pyridone-3-carbamoyl derivatives preparation among the patent documentation 1-3 and by the preparation method of this intermediate preparation 2-pyridone-3-carbamoyl derivatives; but can see that also reaction yield and/or the operation etc. that obtains compound with high purity also should improve.
Patent documentation 1: international the 02/53543rd brochure that discloses
Patent documentation 2: international the 2006/046778th brochure that discloses
Patent documentation 3: international the 2005/073222nd brochure that discloses
Summary of the invention
The invention provides simple and convenient preparation method with the active 2-pyridone of cannabinoid receptor agonists-3-carbamoyl derivatives and important intermediate 1-replacement-2-pyridone-3-carboxylic acid derivatives thereof.
The inventor has carried out deep research at above-mentioned situation, found that can easy, high yield and high purity obtain to have the excellent active 2-pyridone of the cannabinoid receptor agonists-3-carbamoyl derivatives and the method for important intermediate 1-replacement-2-pyridone-3-carboxylic acid derivatives thereof.
That is, the present invention relates to
1) preparation method of the compound shown in the general formula (II), the method includes the steps of:
Steps A with the compound hydrolysis shown in the general formula (I):
(in the formula, R 1Be the alkyl that can be replaced by non-reacted substituting group, the alkenyl that can be replaced by non-reacted substituting group or the alkynyl that can be replaced by non-reacted substituting group;
R 2And R 3Independent separately, be alkyl, alkoxyalkyl or alkoxyl group; Perhaps
R 2And R 3Can form cyclenes with adjacent carbon atom;
R 4Be hydrogen atom or hydroxyl; And
R 5Be alkyl); With
Add alcohol in the hydrolyzate of the compound shown in the general formula that in steps A, generates (I), obtain the step B of the compound shown in the general formula (II):
Figure G2007800518019D00022
(in the formula, R 1, R 2, R 3And R 4Implication same as described above).
Should illustrate that steps A can carried out in the presence of the acid or in the presence of the alkali.When in the presence of alkali, carrying out steps A, can after with alkaline purification, add acid.In addition, can add acid among the step B.
The invention further relates to shown below 2)-18).
2) 1) described preparation method is characterized in that, carries out steps A and step B continuously.
3) 1) or 2) described preparation method, the method includes the steps of:
The step C of the compound reaction shown in compound shown in the general formula (III) and the general formula (IV):
R 1-NH 2??(III)
(in the formula, R 1With 1) implication is identical);
Figure G2007800518019D00031
(in the formula, R 2And R 3With 1) implication is identical);
And, generate the step D of the compound shown in the general formula (I) with the compound and the reaction of the compound shown in the logical formula V that generate among the step C:
Figure G2007800518019D00032
(in the formula, R 4And R 5With 1) implication is identical, R 6The expression alkyl);
(in the formula, R 1, R 2, R 3, R 4And R 5With 1) implication is identical).
4) 3) described preparation method, wherein R 6It is the C1-C2 alkyl.
5) each described preparation method, wherein R 1)-4) 5It is the C1-C2 alkyl.
6) preparation method of the compound shown in the general formula (VIII):
Figure G2007800518019D00034
(in the formula, R 1, R 2, R 3And R 4With 1) implication is identical,
R 7Be hydrogen atom or alkyl,
X is for can get involved heteroatoms, the alkylidene group that can be replaced by non-reacted substituting group, can get involved heteroatoms, the alkenylene that can be replaced by non-reacted substituting group, can get involved heteroatoms, the alkynylene that can be replaced by non-reacted substituting group, cycloalkanes two bases that can be replaced by non-reacted substituting group, cyclenes two bases that can be replaced by non-reacted substituting group, aromatic hydrocarbons two bases that can be replaced by non-reacted substituting group, assorted aromatic hydrocarbons two bases that can be replaced by non-reacted substituting group, or non-aromatic heterocyclic two bases that can be replaced by non-reacted substituting group
Y is singly-bound, the alkylidene group that can be replaced by non-reacted substituting group, the alkenylene that can be replaced by non-reacted substituting group or the alkynylene that can be replaced by non-reacted substituting group),
The method includes the steps of:
The step C of the compound reaction shown in compound shown in the general formula (III) and the general formula (IV):
R 1-NH 2??(III)
(in the formula, R 1With 1) implication is identical);
Figure G2007800518019D00041
(in the formula, R 2And R 3With 1) implication is identical);
And, generate the step D of the compound shown in the general formula (I) with the compound and the reaction of the compound shown in the logical formula V that generate among the step C:
Figure G2007800518019D00042
(in the formula, R 4And R 5With 1) implication is identical, R 6With 3) implication is identical);
Figure G2007800518019D00043
(in the formula, R 1, R 2, R 3, R 4And R 5With 1) implication is identical);
Steps A with the compound hydrolysis shown in the general formula (I);
In the hydrolyzate of the compound shown in the general formula that in steps A, generates (I), add alcohol, obtain the step B of the compound shown in the general formula (II):
Figure G2007800518019D00051
(in the formula, R 1, R 2, R 3And R 4With 1) implication is identical);
With compound shown in the general formula (II) and halide reagent reaction, generate the step e of the compound shown in the general formula (VI):
Figure G2007800518019D00052
(in the formula, R 1, R 2, R 3And R 4With 1) implication is identical, Hal is a halogen atom);
And with the reaction of the compound shown in compound shown in the general formula (VI) and the general formula (VII), the step F of the reaction that is hydrolyzed as required:
Figure G2007800518019D00053
(in the formula, R 7, X, Y be identical with above-mentioned implication).
7) 6) described preparation method is characterized in that, carries out step e and F continuously.
8) 6) or 7) described preparation method, wherein, Hal is the chlorine atom.
9) each described preparation method 6)-8), wherein, R 7Be the C1-C2 alkyl.
10) each described preparation method 6)-9), wherein, X is alkylidene group, cycloalkanes two bases, aromatic hydrocarbons two bases, assorted aromatic hydrocarbons two bases or non-aromatic heterocyclic two bases.
11) each described preparation method 6)-10), wherein, Y is singly-bound or alkylidene group.
12) each described preparation method is characterized in that 3)-11), carries out step C, D, A and B continuously.
13) each described preparation method 1)-12) wherein, obtains the compound shown in the general formula (II) with the crystalline form.
14) each described preparation method 1)-13), wherein, R 4Be hydrogen atom.
15) each described preparation method 1)-14), wherein, R 2Be C1-C3 alkyl or C1-C3 alkoxyl group.
16) each described preparation method 1)-15), wherein, R 3Be C1-C3 alkyl or C1-C3 alkoxy C 1-C3 alkyl.
17) each described preparation method 1)-15), wherein, R 2And R 3Form cyclooctene with adjacent carbon atom.
18) each described preparation method 1)-17), wherein, R 1Be the alkyl that can be replaced by non-reacted substituting group.
19) 1)-16) and 18) in each described preparation method, wherein, R 1Be the alkyl that can be replaced by non-reacted substituting group, R 2Be C1-C3 alkyl, R 3Be C1-C3 alkyl, R 4Be hydrogen atom, R 5Be the C1-C2 alkyl.
20) 1)-14) and 17)-18) in each described preparation method, wherein, R 1Be the alkyl that can be replaced by non-reacted substituting group, R 2And R 3Form cyclooctene with adjacent carbon atom, R 4Be hydrogen atom, R 5Be the C1-C2 alkyl.
21) each described preparation method 1)-20), wherein, the alcohol that adds in the hydrolyzate is Virahol.
22) the crystalline preparation method of compound shown in the general formula (II) is characterized in that, adds alcohol in the solution that contains compound shown in the general formula (II):
Figure G2007800518019D00061
(in the formula, R 1, R 2, R 3And R 4With claim 1) implication is identical).
Should illustrate, solvent in the above-mentioned solution can be used alone or as a mixture the solvent that is selected from aromatic hydrocarbons (for example toluene, dimethylbenzene), alphatic carboxylic acid ester class (for example ethyl acetate, methyl acetate, butylacetate), ethers (for example diethyl ether, tetrahydrofuran (THF)), ketone (for example acetone, ethyl methyl ketone), N,N-dimethylacetamide, N-Methyl pyrrolidone and the water.
23) 22) described preparation method, wherein, alcohol is Virahol.
The present invention also comprises following (1)-(19).
(1) preparation method of the compound shown in the general formula (X), the method includes the steps of:
Steps A a with the compound hydrolysis shown in the general formula (IX):
Figure G2007800518019D00071
(in the formula, R 1aBe the alkyl that can be replaced by non-reacted substituting group, the alkenyl that can be replaced by non-reacted substituting group or the alkynyl that can be replaced by non-reacted substituting group,
R 2aAnd R 3aIndependent separately, be alkyl, alkoxyalkyl or alkoxyl group, perhaps
R 2aAnd R 3aCan form cyclenes with adjacent carbon atom,
R 4aBe hydrogen atom or hydroxyl, and
R 5aBe alkyl); With
Add alcohol shown in the general formula that in steps A a, generates (IX) in the hydrolyzate of compound, generate the crystalline step Ba of the compound shown in the general formula (X):
Figure G2007800518019D00072
(in the formula, R 1a, R 2a, R 3aAnd R 4aIdentical with above-mentioned implication).
Should illustrate that steps A a can carry out in the presence of acid or in the presence of the alkali.When in the presence of alkali, carrying out steps A a, can after with alkaline purification, add acid.
(2) (1) described preparation method is characterized in that, carries out steps A a and step Ba continuously.
(3) (1) or (2) described preparation method, the method includes the steps of:
Step Ca with the reaction of the compound shown in compound shown in the general formula (XI) and the general formula (XII):
R 1a-NH 2??(XI)
(in the formula, R 1aIdentical with (1) implication);
Figure G2007800518019D00081
(in the formula, R 2aAnd R 3aIdentical with (1) implication);
With compound and the reaction of the compound shown in the general formula (XIII) that generates among the step Ca, generate the step Da of the compound shown in the general formula (IX):
Figure G2007800518019D00082
(in the formula, R 4aAnd R 5aIdentical with (1) implication, R 6Be alkyl);
Figure G2007800518019D00083
(in the formula, R 1a, R 2a, R 3a, R 4aAnd R 5aIdentical with (1) implication).
(4) (3) described preparation method is characterized in that, carries out continuously according to the order of step Ca, Da, Aa and Ba.
(5) (3) or (4) described preparation method, wherein R 6aBe the C1-C2 alkyl.
(6) each described method in (1)-(5), wherein, R 5aBe the C1-C2 alkyl.
(7) preparation method of compound shown in the general formula (XVI):
Figure G2007800518019D00084
(in the formula, R 1a, R 2a, R 3aAnd R 4aIdentical with (1) implication, R 7aBe hydrogen atom or alkyl,
X aFor getting involved heteroatoms, the alkylidene group that can be replaced by non-reacted substituting group, can get involved heteroatoms, the alkenylene that can be replaced by non-reacted substituting group, can get involved heteroatoms, the alkynylene that can be replaced by non-reacted substituting group, cycloalkanes two bases that can be replaced by non-reacted substituting group, cyclenes two bases that can be replaced by non-reacted substituting group, aromatic hydrocarbons two bases that can be replaced by non-reacted substituting group, assorted aromatic hydrocarbons two bases that can be replaced by non-reacted substituting group, non-aromatic heterocyclic two bases that can be replaced by non-reacted substituting group
Y aBe singly-bound, the alkylidene group that can be replaced by non-reacted substituting group, the alkenylene that can be replaced by non-reacted substituting group or the alkynylene that can be replaced by non-reacted substituting group),
The method includes the steps of:
Step Ca with compound shown in the general formula (XI) and general formula (XII) reaction:
R 1a-NH 2(XI)
(in the formula, R 1aIdentical with (1) implication);
Figure G2007800518019D00091
(in the formula, R 2aAnd R 3aIdentical with (1) implication);
With compound and the reaction of the compound shown in the general formula (XIII) that generates among the step Ca, generate the step Da of the compound shown in the general formula (IX):
(in the formula, R 4aAnd R 5aIdentical with (1) implication, R 6aIdentical with (3) implication);
(in the formula, R 1a, R 2a, R 3a, R 4aAnd R 5aIdentical with (1) implication);
Steps A a with the compound hydrolysis shown in the general formula (IX);
Add alcohol in the hydrolyzate of the compound shown in the general formula that in steps A a, generates (IX), obtain the step Ba of the compound shown in the general formula (X):
(in the formula, R 1a, R 2a, R 3aAnd R 4aIdentical with (1) implication);
With compound shown in the general formula (X) and halide reagent reaction, generate the step e a of the compound shown in the general formula (XIV):
Figure G2007800518019D00102
(in the formula, R 1a, R 2a, R 3aAnd R 4aIdentical with (1) implication, Hal aBe halogen atom); With
With the reaction of the compound shown in compound shown in the general formula (XIV) and the general formula (XV), the step F a of the reaction that is hydrolyzed as required:
Figure G2007800518019D00103
(in the formula, R 7a, X a, Y aIdentical with above-mentioned implication).
(8) (7) described preparation method is characterized in that, carries out step Ca, Da, Aa and Ba continuously.
(9) (7) described preparation method is characterized in that, carries out step e a and Fa continuously.
(10) each described preparation method in (7)-(9), wherein, Hal aBe the chlorine atom.
(11) each described preparation method in (7)-(10), wherein, R 7aBe the C1-C2 alkyl.
(12) each described preparation method in (7)-(11), wherein, X aBe alkylidene group, cycloalkanes two bases, aromatic hydrocarbons two bases, assorted aromatic hydrocarbons two bases, non-aromatic heterocyclic two bases.
(13) each described preparation method in (7)-(12), wherein, Y aBe singly-bound or alkylidene group.
(14) each described preparation method in (1)-(13), wherein, R 4aBe hydrogen atom.
(15) each described preparation method in (1)-(14), wherein, R 2aBe C1-C2 alkyl or C1-C2 alkoxyl group.
(16) each described preparation method in (1)-(15), wherein, R 3aBe C1-C3 alkyl or C1-C2 alkoxy C 1-C2 alkyl.
(17) each described preparation method in (1)-(14), wherein, R 2aAnd R 3aForm cyclooctene with adjacent carbon atom.
(18) each described preparation method in (1)-(17), wherein, R 1aBe the alkyl that can be replaced by non-reacted substituting group.
(19) each described preparation method in (1)-(18), wherein, the alcohol that adds in the hydrolyzate is Virahol.
The implication of each term below is described.Each term uses with unified implication in this manual, also uses with identical implication when being used in combination when using separately or with other term.
In this specification sheets, " heteroatoms " is meant Sauerstoffatom, sulphur atom, nitrogen-atoms.
In this specification sheets, " halogen atom " is meant fluorine atom, chlorine atom, bromine atoms or iodine atom.
In this specification sheets, " alkyl " comprises the monovalence alkyl of the straight or branched of carbonatoms 1-8.For example have: methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, isohexyl, n-heptyl, n-octyl etc., preferred C1-C6 alkyl.When particularly specifying carbonatoms, be meant " alkyl " of carbonatoms with this number range.
R 1And R 1a" alkyl " preferred C1-C6 alkyl.
R 2And R 2a" alkyl " preferred C1-C4 alkyl, further preferred C1-C3 alkyl, most preferably C1-C2 alkyl.
R 3And R 3a" alkyl " preferred C1-C4 alkyl.
R 5And R 5a" alkyl " preferred C1-C4 alkyl, further preferred C1-C3 alkyl.
R 6And R 6a" alkyl " preferred C1-C4 alkyl, further preferred C1-C2 alkyl.
The different carbon atom that " alkoxyalkyl " is meant above-mentioned " alkyl " in this specification sheets is replaced the group of gained by 1 or 2 following " alkoxyl group ".Methyl oxygen ylmethyl, ethyl oxygen ylmethyl, n-propyl oxygen ylmethyl, sec.-propyl oxygen ylmethyl, normal-butyl oxygen ylmethyl, 2-methyl oxygen base ethyl, 2-ethyl oxygen base ethyl, 2-n-propyl oxygen base ethyl, 1-sec.-propyl oxygen base ethyl, 1-normal-butyl oxygen base ethyl, 3-methyl oxygen base propyl group, 3-ethyl oxygen base propyl group, 3-n-propyl oxygen base propyl group, 2-sec.-propyl oxygen base propyl group, 2-normal-butyl oxygen base propyl group etc. are for example arranged.Preferred C1-C4 alkyl oxy C1-C4 alkyl, further preferred C1-C2 alkyl oxy C1-C2 alkyl.When particularly specifying carbonatoms, be meant " alkyl oxy alkyl " with the carbonatoms in this number range.
R 2And R 2a" alkyl oxy alkyl " preferred C1-C4 alkyl oxy C1-C4 alkyl, further preferred C1-C2 alkyl oxy C1-C2 alkyl.
R 3And R 3a" alkyl oxy alkyl " preferred C1-C4 alkyl oxy C1-C4 alkyl, further preferred C1-C2 alkyl oxy C1-C2 alkyl.
In this specification sheets, " alkenyl " comprises carbonatoms is 2-8, have the two keys more than 1 or 2, the monovalence alkyl of straight or branched.Vinyl, allyl group, 1-propenyl, crotyl, pentenyl, 2-hexenyl, 2-heptenyl, 2-octenyl etc. are for example arranged.Preferred C2-C6 alkenyl.When specifying carbonatoms, be meant " alkenyl " of carbonatoms with this number range.
R 1And R 1a" alkenyl " preferred C2-C6 alkenyl.
In this specification sheets, " alkynyl " comprises carbonatoms is 2-8, have the triple-linked straight or branched monovalence alkyl more than 1 or 2.For example have: ethynyl, 1-proyl, 2-propynyl, 2-butyne base, valerylene base, 2-hexin base, 2-heptyne base, 2-octyne base etc.Preferred C2-C6 alkynyl.When specifying carbonatoms, be meant " alkynyl " of carbonatoms with this number range.
R 1And R 1a" alkynyl " preferred C2-C6 alkynyl.
In this specification sheets, " cycloalkyl " comprises carbon atom is the individual cycloalkyl of 3-8.For example have: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group.Preferred C3-C6 cycloalkyl.When specifying carbonatoms, be meant " cycloalkyl " of carbonatoms with this number range.
" cycloalkenyl group " comprises carbonatoms 3-8 loop chain alkene in this specification sheets.For example have: cyclopropenyl radical, cyclobutene base, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctene base.Preferred C3-C6 cycloalkenyl group.When specifying carbonatoms, be meant " cycloalkenyl group " of carbonatoms with this number range.
In this specification sheets, " R 2And R 3Can form cyclenes with adjacent carbon atom " in " cyclenes " only comprise at R 2Adjacent carbon atom and R 3Have the cyclenes of the 5-10 unit ring of 1 two key between the adjacent carbon atom.For example have: cyclopentenes, tetrahydrobenzene, suberene, cyclooctene, cyclonoene and cyclodecene.Preferred C5-C8 cyclenes, further preferred cyclooctene.When specifying carbonatoms, be meant " cycloalkenyl group " of carbonatoms with this number range.
In this specification sheets, " R 2aAnd R 3aCan form cyclenes with adjacent carbon atom " in " cyclenes " only comprise at R 2aAdjacent carbon atom and R 3aHave the cyclenes of the 5-10 unit ring of 1 two key between the adjacent carbon atom.For example have: cyclopentenes, tetrahydrobenzene, suberene, cyclooctene, cyclonoene and cyclodecene.Preferred C5-C8 cyclenes, further preferred cyclooctene.When specifying carbonatoms, be meant " cycloalkenyl group " of carbonatoms with this number range.
In this specification sheets, " alkyl oxy " is meant has one above-mentioned " alkyl " to replace the group that obtains on the Sauerstoffatom.For example have: methyl oxygen base, ethyl oxygen base, n-propyl oxygen base, sec.-propyl oxygen base, normal-butyl oxygen base, isobutyl-oxygen base, sec-butyl oxygen base, tertiary butyl oxygen base, n-pentyl oxygen base, isopentyl oxygen base, 2-amyl group oxygen base, 3-amyl group oxygen base, n-hexyl oxygen base, isohexyl oxygen base, 2-hexyl oxygen base, 3-hexyl oxygen base, n-heptyl oxygen base, n-octyl oxygen base etc.Preferred C1-C6 alkyl oxy.Further preferred C1-C4 alkyl oxy.When specifying carbonatoms, be meant " alkyl oxy " of carbonatoms with this number range.
R 2And R 2a" alkyl oxy " preferred C1-C4 alkyl oxy, further preferred C1-C2 alkyl oxy.
R 3And R 3a" alkyl oxy " preferred C1-C4 alkyl oxy.
" alkenyl oxy " is meant the group that has 1 " alkenyl " to replace in this specification sheets on Sauerstoffatom.For example have: vinyl oxygen base, allyl group oxygen base, 1-propenyl oxygen base, crotyl oxygen base, pentenyl oxygen base, 2-hexenyl oxygen base, 2-heptenyl oxygen base, 2-octenyl oxygen base etc.Preferred C2-C6 alkenyl oxy.Further preferred C2-C4 alkenyl oxy.When specifying carbonatoms, be meant " alkenyl oxy " of carbonatoms with this number range.
In this specification sheets, " alkynyloxy base " is meant the group that has 1 above-mentioned " thiazolinyl " to replace on the Sauerstoffatom.For example have: ethynyl oxygen base, 1-proyl oxygen base, 2-propynyl oxygen base, 2-butyne base oxygen base, valerylene base oxygen base, the own alkynyloxy base of 2-, 2-alkynyloxy in heptan base, the hot alkynyloxy base of 2-etc.Preferred C2-C6 alkynyloxy base.Further preferred C2-C4 alkynyloxy base.When specifying carbonatoms, be meant " the alkynyloxy base " of carbonatoms with this number range.
In this specification sheets, " cycloalkyl oxy " is meant the group that has 1 above-mentioned " cycloalkyl " to replace on the Sauerstoffatom.For example have: cyclopropyl oxygen base, cyclobutyl oxygen base, cyclopentyloxy, cyclohexyl oxygen base, suberyl oxygen base, ring octyl group oxygen base.Preferred C3-C6 cycloalkyl oxy.When specifying carbonatoms, be meant " cycloalkyl oxy " of carbonatoms with this number range.
In this specification sheets, " alkylthio " is meant the group that has 1 " alkyl " to replace on the sulphur atom.Methylthio group, ethylmercapto group, positive rosickyite base, iprotiazem base, positive butylthio, isobutyl sulfenyl, secondary butylthio, uncle's butylthio, positive penta sulfenyl, isoamyl sulfenyl, 2-penta sulfenyl, 3-penta sulfenyl, just own sulfenyl, dissident's sulfenyl, the own sulfenyl of 2-, the own sulfenyl of 3-, positive heptan sulfenyl, positive hot sulfenyl etc. are for example arranged.Preferred C1-C6 alkylthio.Further preferred C1-C4 alkylthio.When specifying carbonatoms, be meant " alkylthio " of carbonatoms with this number range.
In this specification sheets, " alkenyl thio " is meant the group that has 1 " alkenyl " to replace on the sulphur atom.For example have: vinyl sulfenyl, allyl group sulfenyl, 1-propenyl sulfenyl, crotyl sulfenyl, pentenyl sulfenyl, 2-hexenyl sulfenyl, 2-heptenyl sulfenyl, 2-octenyl sulfenyl etc.Preferred C2-C6 alkenyl thio.Further preferred C2-C4 alkenyl thio.When specifying carbonatoms, be meant " alkenyl thio " of carbonatoms with this number range.
In this specification sheets, " alkynyl sulfenyl " is meant the group that has 1 " alkynyl " to replace on the sulphur atom.For example have: ethynyl sulfenyl, 1-proyl sulfenyl, 2-propynyl sulfenyl, 2-butyne base sulfenyl, valerylene base sulfenyl, 2-hexin base sulfenyl, 2-heptyne base sulfenyl, 2-octyne base sulfenyl etc.Preferred C2-C6 alkynyl sulfenyl.Further preferred C2-C4 alkynyl sulfenyl.When specifying carbonatoms, be meant " the alkynyl sulfenyl " of carbonatoms with this number range.
In this specification sheets, " cycloalkylthio " comprises the group that has 1 above-mentioned " cycloalkyl " to replace on the sulphur atom.For example have: ring rosickyite base, ring butylthio, ring penta sulfenyl, hexamethylene sulfenyl, ring sulfenyl in heptan, cyclooctasulfur base.Preferred C3-C6 cycloalkylthio.When specifying carbonatoms, be meant " cycloalkylthio " of carbonatoms with this number range.
In this specification sheets, " alkylidene group " is meant the alkylidene group of the straight or branched of carbonatoms 1-10.For example have: methylene radical, 1-methyl methylene radical, 1,1-dimethylated methylene base, ethylidene, 1-methyl ethylidene, 1-ethyl ethylidene, 1,1-dimethyl ethylidene, 1,2-dimethyl ethylidene, 1,1-diethyl ethylidene, 1,2-diethyl ethylidene, 1-ethyl-2-methyl ethylidene, propylidene, 1-methyl propylidene, 2-methyl propylidene, 1,1-dimethyl propylidene, 1,2-dimethyl propylidene, 2,2-dimethyl propylidene, 1-ethyl propylidene, 2-ethyl propylidene, 1,1-diethyl propylidene, 1,2-diethyl propylidene, 2,2-diethyl propylidene, 2-ethyl-2-methyl propylidene, butylidene, 1-methyl butylidene, 2-methyl butylidene, 1,1-dimethyl butylidene, 1,2-dimethyl butylidene, 2,2-dimethyl butylidene, 2,2-di propylidene, 1-isobutyl-ethylidene, 1-(2, the 2-dimethyl propyl) methylene radical, 1-tertiary butyl ethylidene, 1-isobutyl-propylidene etc.When specifying carbonatoms, be meant " alkylidene group " of carbonatoms with this number range.
In this specification sheets, " alkylidene group that can get involved heteroatoms, can be replaced by non-reacted substituting group " be meant following " alkylidene group that can be replaced by non-reacted substituting group " alkylidene group methylene moiety can by above-mentioned " heteroatoms " at non-conterminous 1 place or 2 places replace the group of gained." can get involved heteroatomic alkylidene group " for example has: methylene radical, 1-methyl methylene radical, 1,1-dimethylated methylene base, ethylidene, 1-methyl ethylidene, 1-ethyl ethylidene, 1,1-dimethyl ethylidene, 1,2-dimethyl ethylidene, 1,1-diethyl ethylidene, 1,2-diethyl ethylidene, 1-ethyl-2-methyl ethylidene, propylidene, 1-methyl propylidene, 2-methyl propylidene, 1,1-dimethyl propylidene, 1,2-dimethyl propylidene, 2,2-dimethyl propylidene, 1-ethyl propylidene, 2-ethyl propylidene, 1,1-diethyl propylidene, 1,2-diethyl propylidene, 2,2-diethyl propylidene, 2-ethyl-2-methyl propylidene, butylidene, 1-methyl butylidene, 2-methyl butylidene, 1,1-dimethyl butylidene, 1,2-dimethyl butylidene, 2,2-dimethyl butylidene, 2,2-di propylidene, 1-isobutyl-ethylidene, 1-(2, the 2-dimethyl propyl) methylene radical, 1-tertiary butyl ethylidene, 1-isobutyl-propylidene, methylene radical oxygen methylene, the sulfonium methylide methylene, methylene radical (N-methylamino) methylene radical, the ethyleneoxy group methylene radical, ethylidene sulfenyl methylene radical, ethylidene (N-methylamino) methylene radical, methylene radical oxygen base ethylidene, methylene radical sulfenyl ethylidene, methylene radical (N-methylamino) ethylidene, propylidene oxygen methylene, propylidene oxygen base ethylidene, propylidene oxygen base propylidene, 1-isobutyl-methylene radical oxygen methylene, 1-(2, the 2-dimethyl propyl) methylene radical oxygen methylene, 1-tertiary butyl methylene radical oxygen methylene, 1-isobutyl-ethyleneoxy group methylene radical, 1-isobutyl-methylene radical oxygen base ethylidene etc.When specifying carbonatoms, be meant " can get involved heteroatomic alkylidene group " of the carbonatoms with this number range.
In this specification sheets, " alkenylene " is meant the straight or branched alkenylene of carbonatoms 2-10.For example have: vinylidene, 1-methyl vinylidene, 1-ethyl vinylidene, 1,2-dimethyl vinylidene, 1,2-diethyl vinylidene, 1-ethyl-2-methyl vinylidene, propenylidene, 1-methyl-2-propenylidene, 2-methyl-2-propenylidene, 1,1-dimethyl-2-propenylidene, 1,2-dimethyl-2-propenylidene, 1-ethyl-2-propenylidene, 2-ethyl-2-propenylidene, 1,1-diethyl-2-propenylidene, 1,2-diethyl-2-propenylidene, the 1-crotonylidene, the 2-crotonylidene, 1-methyl-2-crotonylidene, 2-methyl-2-crotonylidene, 1,1-dimethyl-2-crotonylidene, 1,2-dimethyl-2-crotonylidene, 1-isobutyl-vinylidene, 1-(2, the 2-dimethyl propyl)-2-propenylidene, the 1-tertiary butyl-2-propenylidene, 1-isobutyl--2-propenylidene etc.When specifying carbonatoms, be meant " alkenylene " of carbonatoms with this number range.
" alkenylene that can get involved heteroatoms, can be replaced by non-reacted substituting group " be meant following " alkenylene that can be replaced by non-reacted substituting group " alkenylene methylene moiety can by above-mentioned " heteroatoms " at non-conterminous 1 place or 2 places replace the group of gained." can get involved heteroatomic alkenylene " has: vinylidene, 1-methyl vinylidene, 1-ethyl vinylidene, 1,2-dimethyl vinylidene, 1,2-diethyl vinylidene, 1-ethyl-2-methyl vinylidene, propenylidene, 1-methyl-2-propenylidene, 2-methyl-2-propenylidene, 1,1-dimethyl-2-propenylidene, 1,2-dimethyl-2-propenylidene, 1-ethyl-2-propenylidene, 2-ethyl-2-propenylidene, 1,1-diethyl-2-propenylidene, 1,2-diethyl-2-propenylidene, the 1-crotonylidene, the 2-crotonylidene, 1-methyl-2-crotonylidene, 2-methyl-2-crotonylidene, 1,1-dimethyl-2-crotonylidene, 1,2-dimethyl-2-crotonylidene, 1-isobutyl-vinylidene, 1-(2, the 2-dimethyl propyl)-the 2-propenylidene, the 1-tertiary butyl-2-propenylidene, 1-isobutyl--2-propenylidene, 1-methyl-2-crotonylidene oxygen methylene, 1-isobutyl--2-crotonylidene oxygen methylene, 1-(2, the 2-dimethyl propyl)-2-crotonylidene oxygen methylene, the 1-tertiary butyl-2-crotonylidene oxygen methylene etc.When specifying carbonatoms, be meant " can get involved heteroatomic alkenylene " of the carbonatoms with this number range.
In this specification sheets, " alkynylene " is meant the straight or branched alkynylene of carbonatoms 2-10.For example have: ethynylene, inferior proyl, the inferior proyl of 1-methyl-2-, the inferior proyl of 1-ethyl-2-, butynelene, 1-methyl-2-butynelene, 2-methyl-3-butynelene, 1,1-dimethyl-2-butynelene, 1,2-dimethyl-3-butynelene, 2,2-dimethyl-3-butynelene, 1-isobutyl-ethynylene, 1-(2, the 2-dimethyl propyl)-Ya proyl, the 1-tertiary butyl-Ya proyl, 1-isobutyl--Ya proyl etc.When specifying carbonatoms, be meant " alkynylene " of carbonatoms with this number range.
In this specification sheets, " alkynylene that can get involved heteroatoms, can be replaced by non-reacted substituting group " be meant following " alkynylene that can be replaced by non-reacted substituting group " alkynylene methylene moiety can by above-mentioned " heteroatoms " at non-conterminous 1 place or 2 places replace the group of gained." can get involved heteroatomic alkynylene " for example has: ethynylene, inferior proyl, the inferior proyl of 1-methyl-2-, the inferior proyl of 1-ethyl-2-, butynelene, 1-methyl-2-butynelene, 2-methyl-3-butynelene, 1,1-dimethyl-2-butynelene, 1,2-dimethyl-3-butynelene, 2,2-dimethyl-3-butynelene, 1-isobutyl-ethynylene, 1-(2, the 2-dimethyl propyl)-the Ya proyl, the 1-tertiary butyl-Ya proyl, 1-isobutyl--Ya proyl, 1-methyl-2-butynelene oxygen methylene, 1-isobutyl--2-butynelene oxygen methylene, 1-(2, the 2-dimethyl propyl)-2-butynelene oxygen methylene, the 1-tertiary butyl-2-butynelene oxygen methylene etc.When specifying carbonatoms, be meant " can get involved heteroatomic alkynylene " of the carbonatoms with this number range.
In this specification sheets, " aryl " comprises monocycle shape or condensation ring-type aromatic hydrocarbon.They can with above-mentioned " cycloalkyl ", above-mentioned " cycloalkenyl group ", aftermentioned " non-aromatic heterocycle " condensation on all possible positions.Aryl be monocycle and condensed ring in any case all can combination on possible position.For example have: phenyl, 1-naphthyl, 2-naphthyl, anthryl, tetralyl, 1,3-benzo dioxolyl, 1,4-benzo dioxacyclohexyl etc.Preferred phenyl, 1-naphthyl, 2-naphthyl, further preferred phenyl.
In this specification sheets, " heteroaryl " comprises the 5-6 unit aromatic ring that ring contains Sauerstoffatom, sulphur atom or nitrogen-atoms more than 1.They can with above-mentioned " cycloalkyl ", above-mentioned " aryl ", aftermentioned " non-aromatic heterocycle " or the condensation on all possible positions of other heteroaryl.Heteroaryl be monocycle and condensed ring in any case all can combination on possible position.For example have: pyrryl (1-pyrryl for example, the 2-pyrryl, the 3-pyrryl), furyl (2-furyl for example, the 3-furyl), thienyl (2-thienyl for example, the 3-thienyl), imidazolyl (2-imidazolyl for example, the 4-imidazolyl), pyrazolyl (1-pyrazolyl for example, the 3-pyrazolyl), isothiazolyl (for example 3-isothiazolyl) isoxazolyl (for example 3-isoxazolyl) oxazolyl (for example 2-oxazolyl), thiazolyl (for example 2-thiazolyl), pyridyl (2-pyridyl for example, the 3-pyridyl, the 4-pyridyl), pyrazinyl (for example 2-pyrazinyl), pyrimidyl (2-pyrimidyl for example, the 4-pyrimidyl), pyridazinyl (for example 3-pyridazinyl), tetrazyl (for example 1H-tetrazyl) oxadiazole base (for example 1,3,4-oxadiazole base), thiadiazolyl group (for example 1,3, the 4-thiadiazolyl group), indolizine base (2-indolizine base for example, 6-indolizine base), pseudoindoyl (for example 2-pseudoindoyl), indyl (1-indyl for example, the 2-indyl, the 3-indyl), indazolyl (for example 3-indazolyl), purine radicals (for example 8-purine radicals), quinolizinyl (for example 2-quinolizinyl), isoquinolyl (for example 3-isoquinolyl), quinolyl (2-quinolyl for example, the 5-quinolyl), phthalazinyl (for example 1-phthalazinyl), naphthyridinyl (for example 2-naphthyridinyl), quinolanyl (for example 2-quinolanyl), quinazolyl (for example 2-quinazolyl), cinnolines base (for example 3-cinnolines base), pteridyl (for example 2-pteridyl), carbazyl (2-carbazyl for example, the 4-carbazyl), phenanthridinyl (2-phenanthridinyl for example, the 3-phenanthridinyl), acridyl (1-acridyl for example, the 2-acridyl), dibenzofuran group (1-dibenzofuran group for example, the 2-dibenzofuran group), benzimidazolyl-(for example 2-benzimidazolyl-), benzoisoxazole base (for example 3-benzoisoxazole base) benzoxazolyl (for example 2-benzoxazolyl) Ben Bing oxadiazole base (for example 4-Ben Bing oxadiazole base), benzisothiazole base (for example 3-benzisothiazole base), benzothiazolyl (for example 2-[4-morpholinodithio base), benzofuryl (for example 3-benzofuryl), benzothienyl (for example 2-benzothienyl), dibenzothiophene base (for example 2-dibenzothiophene base), benzo dioxolyl (for example 1,3-benzo dioxolyl) etc.
In this specification sheets, " non-aromatic heterocycle " comprises the non-aromatic heterocycle that ring includes 1 above nitrogen-atoms, can further contain the 3-12 unit ring of Sauerstoffatom and/or sulphur atom.For example have: pyrrolidyl, pyrrolinyl, imidazolidyl, imidazolinyl, pyrazolidyl, pyrazolinyl, piperidyl, dihydropyridine base, tetrahydro pyridyl, piperazinyl, dihydro pyrazinyl, tetrahydrochysene pyrazinyl, dihydro-pyrimidin base, tetrahydro-pyrimidine base and perhydro pyrimidyl etc.
In this specification sheets, " aryloxy " comprises 1 substituent group on the Sauerstoffatom: for example have: phenyl oxygen base, naphthyloxy etc.
In this specification sheets, " arylthio " comprises 1 substituent group on the sulphur atom: for example have: thiophenyl, naphthalene sulfenyl etc.
In this specification sheets, " heteroaryloxy " comprises the group that has 1 " heteroaryl " to replace on the Sauerstoffatom.For example have: pyrryl oxygen base, furyl oxygen base, thienyl oxygen base, imidazolyl oxygen base, pyrazolyl oxygen base, isothiazolyl oxygen base isoxazolyl oxygen base oxazolyl oxygen base, thiazolyl oxygen base, pyridyl oxygen base, pyrazinyl oxygen base, pyrimidyl oxygen base, pyridazinyl oxygen base, tetrazyl oxygen base oxadiazole base oxygen base, thiazoldiazolioxo, indolizine base oxygen base, pseudoindoyl oxygen base, indyl oxygen base, indazolyl oxygen base, purine radicals oxygen base, quinolizinyl oxygen base, isoquinolyl oxygen base, quinolyl oxygen base, phthalazinyl oxygen base, naphthyridinyl oxygen base, quinolanyl oxygen base, quinazolyl oxygen base, cinnolines base oxygen base, pteridyl oxygen base, carbazyl oxygen base, phenanthridinyl oxygen base, acridyl oxygen base, dibenzofuran group oxygen base, benzimidazolyl-oxygen base, benzoisoxazole base oxygen base benzoxazolyl oxygen base Ben Bing oxadiazole base oxygen base, benzisothiazole base oxygen base, benzothiazolyl oxygen base, benzofuryl oxygen base, benzothienyl oxygen base, dibenzothiophene base oxygen base, benzo dioxolyl oxygen base etc., preferred furyl oxygen base, thienyl oxygen base, imidazolyl oxygen base, pyrazolyl oxygen base, isothiazolyl oxygen base isoxazolyl oxygen base oxazolyl oxygen base, thiazolyl oxygen base, pyridyl oxygen base, pyrazinyl oxygen base, pyrimidyl oxygen base, pyridazinyl oxygen base etc.
In this specification sheets, " heteroarylthio " is included in the group that has 1 above-mentioned " heteroaryl " to replace on the sulphur atom.For example have: the pyrryl sulfenyl, the furyl sulfenyl, the thienyl sulfenyl, the imidazolyl sulfenyl, the pyrazolyl sulfenyl, isothiazolyl sulfenyl isoxazolyl sulfenyl oxazolyl sulfenyl, the thiazolyl sulfenyl, the pyridyl sulfenyl, the pyrazinyl sulfenyl, pyrimidine-based sulfur-base, the pyridazinyl sulfenyl, tetrazyl sulfenyl oxadiazole base sulfenyl, the thiadiazolyl group sulfenyl, indolizine base sulfenyl, the pseudoindoyl sulfenyl, the indyl sulfenyl, the indazolyl sulfenyl, the purine radicals sulfenyl, the quinolizinyl sulfenyl, the isoquinolyl sulfenyl, the quinolyl sulfenyl, the phthalazinyl sulfenyl, the naphthyridinyl sulfenyl, the quinolanyl sulfenyl, the quinazolyl sulfenyl, cinnolines base sulfenyl, the pteridyl sulfenyl, the carbazyl sulfenyl, the phenanthridinyl sulfenyl, the acridyl sulfenyl, the dibenzofuran group sulfenyl, the benzimidazolyl-sulfenyl, benzoisoxazole base sulfenyl benzoxazolyl sulfenyl Ben Bing oxadiazole base sulfenyl, benzisothiazole base sulfenyl, the benzothiazolyl sulfenyl, the benzofuryl sulfenyl, the benzothienyl sulfenyl, dibenzothiophene base sulfenyl, benzo dioxolyl sulfenyl etc.Preferred furyl sulfenyl, thienyl sulfenyl, imidazolyl sulfenyl, pyrazolyl sulfenyl, isothiazolyl sulfenyl, isoxazolyl sulfenyl, oxazolyl sulfenyl, thiazolyl sulfenyl, pyridyl sulfenyl, pyrazinyl sulfenyl, pyrimidine-based sulfur-base, pyridazinyl sulfenyl etc.
In this specification sheets, " cycloalkanes two bases " are meant the group of 1 key in addition on above-mentioned " cycloalkyl ".For example have: pentamethylene two bases, hexanaphthene two bases, cyclooctane two bases etc.
In this specification sheets, " cyclenes two bases " are meant the group of 1 key in addition on above-mentioned " cycloalkenyl group ".For example have: 1-cyclopentenes two bases, 1-tetrahydrobenzene two bases, 1-cyclooctene two bases etc.
" aromatic hydrocarbons two bases " are meant in this specification sheets the group of 1 key in addition on above-mentioned " aryl ".For example have: phenylene, naphthalene two bases etc.
In this specification sheets, " assorted aromatic hydrocarbons two bases " are meant the group of 1 key in addition on above-mentioned " heteroaryl ".For example have: pyrroles's two bases, furans two bases, thiophene two bases, pyrazoles two bases, imidazoles two bases, isothiazole two basic isoxazole two basic oxazole two bases, thiazole two bases, pyrazine two bases, pyrimidine two bases, pyridazine two basic oxadiazole two bases, thiadiazoles two bases, indolizine two bases, isoindole two bases, indoles two bases, indazole two bases, purine two bases, quinolizine two bases, isoquinoline 99.9 two bases, quinoline two bases, phthalazines two bases, naphthyridines two bases, quinolane two bases, quinazoline two bases, cinnolines two bases, pteridine two bases, carbazole two bases, phenanthridines two bases, acridine two bases, diphenylene-oxide two basic benzoxazolone two basic benzoxazinone two bases, benzoglyoxaline two bases, benzoisoxazole two basic benzoxazole two basic Ben Bing oxadiazole two bases, benzisothiazole two bases, benzothiazole two bases, cumarone two bases, thionaphthene two bases, dibenzothiophene two bases, benzo two oxa-s penta ring two bases etc.
In this specification sheets, " non-aromatic heterocyclic two bases " are meant the group of 1 key in addition on above-mentioned " non-aromatic heterocycle ".For example have: tetramethyleneimine two bases, pyrroline two bases, imidazolidine two bases, tetrahydroglyoxaline two bases, pyrazolidine two bases, pyrazoline two bases, piperidines two bases, dihydropyridine two bases, tetrahydropyridine two bases, piperazine two bases, dihydro pyrazine two bases, tetrahydrochysene pyrazine two bases, dihydro-pyrimidin two bases, tetrahydropyrimidine two bases, perhydro pyrimidine two bases, tetrahydrofuran (THF) two bases, tetramethylene sulfide two bases, N-crassitude two bases, tetrahydropyrans two bases, N-methyl perhydro pyridine two bases etc.
In this specification sheets, " alkyl that can be replaced by non-reacted substituting group " has: trihalomethyl group, can be by 1-2 cycloalkyl that is selected from the substituting group replacement of substituting group group A, can be by 1-2 cycloalkenyl group that is selected from the substituting group replacement of substituting group group A, can be by 1-2 alkyl oxy that is selected from the substituting group replacement of substituting group group B, can be by 1-2 cycloalkyl oxy that is selected from the substituting group replacement of substituting group group A, can be by 1-2 alkylthio that is selected from the substituting group replacement of substituting group group B, can be by 1-2 cycloalkylthio that is selected from the substituting group replacement of substituting group group A, can be by 1-3 aryl that is selected from the substituting group replacement of substituting group group C, can be by 1-3 heteroaryl that is selected from the substituting group replacement of substituting group group C, can be by 1-3 aryloxy that is selected from the substituting group C replacement of substituting group group, can be by 1-3 heteroaryl oxygen base that is selected from the substituting group replacement of substituting group group C, can be by 1-3 artyl sulfo that is selected from the substituting group replacement of substituting group group C, can be by 1-3 heteroaryl sulfenyl that is selected from the substituting group replacement of substituting group group C, tetramethyleneimine generation, piperidines generation, morpholinoes etc. can be replaced by 1-2 substituting group.
Substituting group group A:C1-C4 alkyl, trihalomethyl group, C1-C4 alkyl oxy, C1-C4 alkylthio, the phenyl that can be replaced by 1-3 substituting group that is selected from substituting group group C, phenoxy group, the heteroaryl that can be replaced by 1-3 substituting group that is selected from substituting group group C
Substituting group group B: trihalomethyl group, C1-C4 alkyl oxy, C1-C4 alkylthio, the phenyl that can be replaced by 1-3 substituting group that is selected from substituting group group C, phenoxy group, the heteroaryl that can be replaced by 1-3 substituting group that is selected from substituting group group C
Substituting group group C: halogen atom, C1-C4 alkyl, trihalomethyl group, C1-C4 alkyl oxy, C1-C4 alkylthio, the phenyl that can be replaced by 1-3 substituting group that is selected from substituting group group C, phenoxy group, the heteroaryl that can be replaced by 1-3 substituting group that is selected from substituting group group C
In this specification sheets, " alkenyl that can be replaced by non-reacted substituting group ", " alkynyl that can be replaced by non-reacted substituting group ", " alkylidene group that can be replaced by non-reacted substituting group ", " alkenylene that can be replaced by non-reacted substituting group ", non-reacted substituting group in " alkynylene that can be replaced by non-reacted substituting group " has: trihalomethyl group, can be by 1-2 cycloalkyl that is selected from the substituting group replacement of above-mentioned substituting group group A, can be by 1-2 cycloalkenyl group that is selected from the substituent A replacement of above-mentioned substituting group group, can be by 1-3 aryl that is selected from the group replacement of above-mentioned substituting group group C, can be selected from heteroaryl that the group of above-mentioned substituting group group C replaces etc. by 1-3, can be by 1-2 substituting group replacement.
In this specification sheets, " cycloalkanes two bases that can be replaced by non-reacted substituting group ", non-reacted substituting group in " cyclenes two bases that can be replaced by non-reacted substituting group " has: the alkyl that can be replaced by 1-2 substituting group that is selected from above-mentioned substituting group group B, trihalomethyl group, can be by 1-2 cycloalkyl that is selected from the substituting group replacement of above-mentioned substituting group group A, can be by 1-2 cycloalkenyl group that is selected from the substituting group replacement of above-mentioned substituting group group A, can be by 1-3 aryl that is selected from the substituting group replacement of above-mentioned substituting group group C, can be selected from heteroaryl that the substituting group of above-mentioned substituting group group C replaces etc. by 1-3, can be by 1-2 substituting group replacement.
In this specification sheets, " aromatic hydrocarbons two bases that can be replaced by non-reacted substituting group ", the substituting group that " assorted aromatic hydrocarbons two bases that can be replaced by non-reacted substituting group " reach in " non-aromatic heterocyclic two bases that can be replaced by non-reacted substituting group " has: halogen atom, can be by 1-2 alkyl that is selected from the substituting group replacement of above-mentioned substituting group group B, trihalomethyl group, can be by 1-2 cycloalkyl that is selected from the substituting group replacement of above-mentioned substituting group group A, can be by 1-2 alkyl oxy that is selected from the substituting group replacement of above-mentioned substituting group group B, can be by 1-2 cycloalkyl oxy that is selected from the substituting group replacement of above-mentioned substituting group group A, can be by 1-2 alkylthio that is selected from the substituting group replacement of above-mentioned substituting group group B, can be by 1-2 cycloalkylthio that is selected from the substituting group replacement of above-mentioned substituting group group A, can be by 1-3 aryl that is selected from the substituting group replacement of above-mentioned substituting group group C, can be by 1-3 heteroaryl that is selected from the substituting group replacement of above-mentioned substituting group group C, can be by 1-3 aryloxy that is selected from the substituting group replacement of above-mentioned substituting group group C, can be by 1-3 heteroaryl oxygen base that is selected from the substituting group replacement of above-mentioned substituting group group C, can be by 1-3 artyl sulfo that is selected from the substituting group replacement of above-mentioned substituting group group C, can can be replaced by 1-2 substituting group by 1-3 heteroaryl sulfenyl that is selected from the substituting group replacement of above-mentioned substituting group group C.
In this specification sheets, " non-reacted substituting group " is meant the substituting group that does not all react in arbitrary step of above-mentioned steps A-F.The above-mentioned substituting group that exemplifies is for example arranged.
In this specification sheets, " hydrolyzate of the compound shown in the general formula (I) " is meant the metal-salt (metal is sodium, potassium or lithium) of the compound shown in the general formula (II) or its carboxylic acid.
In this specification sheets, " hydrolyzate of the compound shown in the general formula (IX) " is meant the metal-salt (metal is sodium, potassium or lithium) of the compound shown in the general formula (X) or its carboxylic acid.
In this specification sheets, " hydrolysis " is included in hydrolysis under the acidic conditions or the hydrolysis under the alkaline condition.During hydrolysis under the alkaline condition, can add acid.
In this specification sheets, " adding alcohol in hydrolyzate " comprises following situation: 1) after the hydrolysis, with the reaction solution organic solvent extraction, add the situation of alcohol to its organic layer; 2) after the hydrolysis, in reaction solution, add organic solvent, layering, the situation of adding alcohol to its water layer; 3) after the hydrolysis, in reaction solution, add acid, use organic solvent extraction then, add the situation of alcohol to its organic layer; 4) after the hydrolysis, in reaction solution, add acid, add organic solvent then, layering, the situation of adding alcohol to its water layer; 5) after the hydrolysis,, add the situation of pure and mild acid to its organic layer with the reaction solution organic solvent extraction; 6) after the hydrolysis, in reaction solution, add organic solvent, layering, the situation of adding pure and mild acid to its water layer.As required, can carry out concentrating and/or dilution of solution.
In this specification sheets, " steps A is reacted continuously with B " is meant and promptly can be used for following step B by the compound that need not to separate generation after the reaction of steps A.
In this specification sheets, " steps A a is reacted continuously with Ba " is meant and promptly can be used for following step Ba by the compound that need not to separate generation after the reaction of steps A a.
In this specification sheets, " step C, D, A and B are reacted continuously " is meant the compound that need not to separate generation after the reaction of each step C, D and A, promptly can be used for following each step D, A and B.
In this specification sheets, " step Ca, Da, Aa and Ba are reacted continuously " is meant the compound that need not to separate generation after the reaction of each step Ca, Da and Aa, promptly can be used for following each step Da, Aa and Ba.
In this specification sheets, " step e is reacted continuously with F " is meant and promptly can be used for following step F by the compound that need not to separate generation after the reaction of step e.
In this specification sheets, " step e a is reacted continuously with Fa " is meant and promptly can be used for following step F a by the compound that need not to separate generation after the reaction of step e a.
General formula (I), (II), (III), (IV), (V), (VI), (VII) and (VIII) shown in the R of compound 1-R 7, X, Y and Hal the preferred substituted group represent by (Ia)-(IIb).Preferred their compound of possible combination.
R 1Preferably (Ia) alkyl that can be replaced by non-reacted substituting group, the alkenyl that can be replaced by non-reacted substituting group or the alkynyl that can be replaced by non-reacted substituting group, further preferred (Ib) alkyl that can be replaced by non-reacted substituting group, most preferably (Ic) can be selected from the alkyl of 1-2 the substituting group replacement of substituting group group D.
Substituting group group D: trifluoromethyl, C1-C4 alkyl oxy, C5-C6 cycloalkyl, the phenyl and the morpholino base that can be replaced by 1-2 halogen atom
R 2Preferably (Id) alkyl, alkyl oxy alkyl or alkyl oxy, further preferred (Ie) alkyl or alkyl oxy, most preferably (If) C1-C3 alkyl.
R 3Preferably (Ig) alkyl, alkyl oxy alkyl or alkyl oxy, further preferred (Ih) alkyl or alkyl oxy alkyl, most preferably (Ii) C1-C3 alkyl.
Also preferred R 2And R 3With adjacent carbon atom, form 5-10 unit cyclenes, more preferably (Ik) cyclooctene that (Ij) has 1 two key.
R 4Preferably (Il) hydrogen atom or hydroxyl, further preferred (Im) hydrogen atom.
R 5Preferred (In) alkyl, further preferred (Io) C1-C2 alkyl.
R 6Preferred (Ip) alkyl, further preferred (Iq) C1-C2 alkyl.
R 7Preferably (Ir) hydrogen atom or alkyl, further preferred (Is) C1-C2 alkyl.
The alkylidene group that X preferred (It) can get involved heteroatoms, can be replaced by non-reacted substituting group, the alkenylene that can get involved heteroatoms, can be replaced by non-reacted substituting group, the alkynylene that can get involved heteroatoms, can be replaced by non-reacted substituting group, cycloalkanes two bases that can be replaced by non-reacted substituting group, cyclenes two bases that can be replaced by non-reacted substituting group, aromatic hydrocarbons two bases that can be replaced by non-reacted substituting group, assorted aromatic hydrocarbons two bases that can be replaced by non-reacted substituting group, non-aromatic heterocyclic two bases that can be replaced by non-reacted substituting group; Further preferred (Iu) alkylidene group that can get involved heteroatoms, can be replaced by non-reacted substituting group, cycloalkanes two bases that can be replaced by non-reacted substituting group, aromatic hydrocarbons two bases that can be replaced by non-reacted substituting group, assorted aromatic hydrocarbons two bases that can be replaced by non-reacted substituting group, non-aromatic heterocyclic two bases that can be replaced by non-reacted substituting group; Most preferably (Iv) cycloalkanes two bases, aromatic hydrocarbons two bases, assorted aromatic hydrocarbons two bases or tetrahydropyrans two bases that can be replaced by halogen atom.
Preferred (Iw) singly-bound of Y, the alkylidene group that can be replaced by non-reacted substituting group, the alkenylene that can be replaced by non-reacted substituting group or the alkynylene that can be replaced by non-reacted substituting group, further preferred (Ix) singly-bound or alkylidene group, most preferably (Iy) singly-bound or (Iz) C1-C2 alkylidene group.
Preferred (IIa) halogen atom of Hal, further preferred (IIb) chlorine atom.
General formula (XI), (X), (XI), (XII), (XIII), (XIV), (XV) and (XVI) shown in the R of compound 1a-R 7a, X a, Y aAnd Hal aThe preferred substituted group represent by (Iaa)-(IIba).Preferred their compound of possible combination.
R 1aPreferably (Iaa) alkyl that can be replaced by non-reacted substituting group, the alkenyl that can be replaced by non-reacted substituting group or the alkynyl that can be replaced by non-reacted substituting group, further preferred (Iba) alkyl that can be replaced by non-reacted substituting group, most preferably (Ica) can be selected from the alkyl of 1-2 the substituting group replacement of substituting group group D.
Substituting group group D a: trifluoromethyl, C1-C4 alkyl oxy, C5-C6 cycloalkyl, the phenyl and the morpholino base that are replaced by 1-2 halogen atom
R 2aPreferably (Ida) alkyl, alkyl oxy alkyl or alkyl oxy, further preferred (Iea) alkyl or alkyl oxy, most preferably (Ifa) C1-C2 alkyl.
R 3aPreferably (Iga) alkyl, alkyl oxy alkyl or alkyl oxy, further preferred (Iha) alkyl or alkyl oxy alkyl, most preferably (Iia) C1-C3 alkyl.
Preferred R 2aAnd R 3aWith adjacent carbon atom, form the 5-10 unit cyclenes that (Ija) has 1 two key, further preferred (Ika) cyclooctene.
R 4aPreferably (Ila) hydrogen atom or hydroxyl, further preferred (Ima) hydrogen atom.
R 5aPreferred (Ina) alkyl, further preferred (Ioa) C1-C2 alkyl.
R 6aPreferred (Ipa) alkyl, further preferred (Iqa) C1-C2 alkyl.
R 7aPreferably (Ira) hydrogen atom or alkyl, further preferred (Isa) C1-C2 alkyl.
X aPreferred (Ita) alkylidene group that can get involved heteroatoms, can be replaced by non-reacted substituting group, the alkenylene that can get involved heteroatoms, can be replaced by non-reacted substituting group, the alkynylene that can get involved heteroatoms, can be replaced by non-reacted substituting group, cycloalkanes two bases that can be replaced by non-reacted substituting group, cyclenes two bases that can be replaced by non-reacted substituting group, aromatic hydrocarbons two bases that can be replaced by non-reacted substituting group, assorted aromatic hydrocarbons two bases that can be replaced by non-reacted substituting group, non-aromatic heterocyclic two bases that can be replaced by non-reacted substituting group; Further preferred (Iua) alkylidene group that can get involved heteroatoms, can be replaced by non-reacted substituting group, cycloalkanes two bases that can be replaced by non-reacted substituting group, aromatic hydrocarbons two bases that can be replaced by non-reacted substituting group, assorted aromatic hydrocarbons two bases that can be replaced by non-reacted substituting group, non-aromatic heterocyclic two bases that can be replaced by non-reacted substituting group; Most preferably (Iva) cycloalkanes two bases, aromatic hydrocarbons two bases, assorted aromatic hydrocarbons two bases or tetrahydropyrans two bases that can be replaced by halogen atom.
Y aPreferably (Iwa) singly-bound, the alkylidene group that can be replaced by non-reacted substituting group, the alkenylene that can be replaced by non-reacted substituting group or the alkynylene that can be replaced by non-reacted substituting group, further preferred (Ixa) singly-bound or alkylidene group, most preferably (Iya) singly-bound or (Iza) C1-C2 alkylidene group.
Hal aPreferred (IIaa) halogen atom, further preferred (IIba) chlorine atom.
The present invention as can easy, high yield and high purity to obtain to have the preparation method of the excellent active 2-pyridone of cannabinoid receptor agonists-3-carbamoyl derivatives and important intermediate thereof effective.
Embodiment
The compounds of this invention can adopt any method shown below synthetic.General formula (I), (II), (III), (IV), (V), (VI), (VII) and (VIII) shown in compound in, when having asymmetric center, comprise racemic modification and/or optically active body.
General formula (I), (II), (III), (IV), (V), (VI), (VII) and (VIII) shown in compound in each step, can exist with the form of suitable salt or solvate.
[changing 29]
Figure G2007800518019D00241
(in the formula, R 1, R 2, R 3, R 4And R 5With 1) implication is identical, R 6With 3) implication is identical, R 7, X, Y and Hal and 6) implication is identical).
Step C is the step of the compound shown in compound shown in the general formula (IV) and the general formula (III) being carried out dehydrating condensation.
This step can be carried out in solvent-free or solvent.
Compound shown in the general formula (III) can use with 0.1-1mol equivalent, preferred 0.35-0.85mol equivalent with respect to the compound shown in the general formula (IV).R 2And R 3Can not with adjacent carbon atom one time-out, can further preferably use the 0.35-0.55mol equivalent.R 2And R 3Can form cyclenes with adjacent carbon atom, can further preferably use the 0.65-0.85mol equivalent.
Reaction solvent can use toluene, dimethylbenzene, chlorobenzene or their mixed solvent, preferred toluene.
Reaction times can carry out with 30 minutes-48 hours, preferred 30 minutes-10 hours.
Temperature of reaction can be carried out under the temperature that the temperature that 50 ℃-reaction solvent refluxes, preferred 100 ℃-reaction solvent reflux.
As required, can use the normal acetate of 0.05-0.10mol with respect to the compound shown in the general formula (IV).
After the reaction of step C finishes, can be directly or concentration of reaction solution as required, be used for step D.The target compound that it should be noted that dehydrating condensation can use conventional purification process to separate, and is used for step D.
Step D carries out closed loop with the compound of step C gained and the compound shown in the logical formula V, generates the step of the compound shown in the general formula (I).
This step can be carried out in solvent-free or solvent.
With respect to the compound shown in the general formula (IV), the compound shown in the logical formula V can use 0.3-1.2mol equivalent, preferred 0.5-1.0mol equivalent.R 2And R 3, can further preferably not use the 0.55-0.75mol equivalent with adjacent carbon atom one time-out.R 2And R 3When forming cyclenes, can further preferably use the 0.85-1.05mol equivalent with carbon atom.
Reaction solvent can use toluene, dimethylbenzene, chlorobenzene or their mixed solvent, preferred toluene.
Reaction times can carry out 30 minutes-48 hours, preferred 30 minutes-16 hours.
Temperature of reaction can be carried out under the temperature that the temperature that 50 ℃-reaction solvent refluxes, preferred 100 ℃-reaction solvent reflux.
The reaction of step D can be directly used in steps A with reaction solution A after finishing, and perhaps concentrates as required, is used for steps A.Compound shown in the general formula (I) can extract by ordinary method with separation and purification after be used for steps A.
Steps A is that the compound shown in the general formula (I) that will obtain among the step D is hydrolyzed, and generates the step of the hydrolyzate of the compound shown in the general formula (I).
Under acidic conditions, during hydrolysis, after the hydrolysis, can in reaction solution, add alcohol, use organic solvent extraction.The reaction solution organic solvent extraction can also be added alcohol then in organic layer.
When under alkaline condition, being hydrolyzed, can in reaction solution, add acid after the hydrolysis, make acidity, in reaction solution, add alcohol then, use organic solvent extraction.Can also in reaction solution, add acid, make acidity, use organic solvent extraction then, in organic layer, add alcohol then.In addition, when hydrolyzate is dissolved in the organic layer, the reaction solution organic solvent extraction can be added pure and mild acid then in organic layer.
After the hydrolysis, reaction solution can be directly used in the step of back, perhaps concentrate as required, be used for the step of back.
Organic solvent ethyl acetate, toluene.
When A) being hydrolyzed under acidic conditions, with respect to the compound shown in the general formula (I), acid can be used the 0.25-10mol equivalent, preferred 1-3mol.
Acid can be used hydrochloric acid or sulfuric acid.Reaction solvent, reaction times, temperature of reaction, crystal are separated out temperature that time, crystal the separates out situation can be with the hydrolysis under alkaline condition of the following stated the time and are used equally.
When B) being hydrolyzed under alkaline condition, with respect to the compound shown in the general formula (I), alkali can use the 0.25-3mol equivalent, preferred 0.8-2.5mol equivalent, further preferred 1.2-2mol equivalent.
Can use sodium hydroxide, potassium hydroxide or lithium hydroxide as alkali, preferred sodium hydroxide.It should be noted that alkali can use with the form of the solid or the aqueous solution.
Reaction solvent can use the mixed solvent of alcohol (methyl alcohol, ethanol, n-propyl alcohol or Virahol)/water or toluene/alcohol (methyl alcohol, ethanol, n-propyl alcohol or Virahol)/water, preferred toluene and methanol/water or methanol.
Reaction times can carry out 0.25-8 hour, preferred 0.5-2 hour.
Temperature of reaction can be carried out under 0 ℃-70 ℃, preferred 20 ℃-60 ℃.
After hydrolysis finishes, can be as required with the reaction solution toluene wash, obtain being dissolved with the layer (water layer or organic layer) of the hydrolyzate of the compound shown in the general formula (I).
The acid that joins in the layer of the hydrolyzate that is dissolved with the compound shown in reaction solution or the general formula (I) can be used hydrochloric acid or sulfuric acid, preferably sulfuric acid.
Step B adds alcohol in the hydrolyzate of the compound shown in the general formula (I) that generates in steps A, generate the crystalline step of the compound shown in the general formula (II).
The alcohol that adds can use methyl alcohol, ethanol, n-propyl alcohol, Virahol or their mixed solvent, preferably uses Virahol.
Crystal can be separated out with 0.25-12 hour, preferred 0.25-2 hour.
Crystal can be separated out under to 5 ℃ at-10 ℃ to 25 ℃, preferred-5 ℃.
It should be noted that step C, D and A need not to separate, can carry out continuously.
Step e is that the compound shown in the general formula (II) is reacted with halogenating agent, generates the step of the compound shown in the general formula (VI).
With respect to the compound shown in the general formula (II), halogenating agent can use 0.5-2mol equivalent, preferred 0.8-1.5mol equivalent.
Reaction solvent can use toluene, tetrahydrofuran (THF), N, dinethylformamide, N-Methyl pyrrolidone or their mixed solvent, preferred toluene/N-Methyl pyrrolidone or tetrahydrofuran (THF)/N, the mixed solvent of dinethylformamide.
Reaction times can carry out 0.25-12 hour, preferred 0.25-2 hour.
Temperature of reaction can adopt 10 ℃-50 ℃, preferred 20 ℃-30 ℃.
After the reaction of step 4 finished, reaction solution can directly or after concentrated as required be used for step F.
Step F is in the presence of alkali, makes the reaction of the compound shown in compound shown in the general formula (VI) and the general formula (VII) or its hydrochlorate, generates the step of the compound shown in the general formula (VIII).
With respect to the compound shown in the general formula (VI), the compound shown in the general formula (VII) or its hydrochlorate can use the 0.5-2mol equivalent, preferred 0.8-1.5mol equivalent.
Hydrochlorate can use hydrochloride, hydrobromate or vitriol, the preferably salt hydrochlorate.
With respect to the compound shown in the general formula (VI), alkali can use the 0.5-2mol equivalent, preferred 0.8-1.5mol equivalent.
Reaction solvent can use toluene, tetrahydrofuran (THF), N, dinethylformamide, N-Methyl pyrrolidone or their mixed solvent, preferred toluene/N-Methyl pyrrolidone or tetrahydrofuran (THF)/N, the mixed solvent of dinethylformamide.
Reaction times can carry out 0.25-12 hour, preferred 0.25-2 hour.
Temperature of reaction can be carried out under 10 ℃-50 ℃, preferred 20 ℃-30 ℃.
R 7During for hydrogen atom, the reaction of step F can be separated out crystal after finishing, and if desired, can also add alcohol and separate out crystal, can also use methyl alcohol, ethanol, n-propyl alcohol, Virahol or their mixed solvent, preferred Virahol.
Crystal can be separated out with 0.25-12 hour, preferred 0.25-2 hour.
Crystal can be separated out at-10 ℃ to 25 ℃, preferred-5 ℃ to 5 ℃.
R 7During for alkyl, same with steps A, under acidic conditions or hydrolysis under the alkaline condition, can obtain R 7Be the compound shown in the general formula (VIII) of hydrogen atom.
Can be as required, B is same with step, adds alcohol crystal is separated out, and can use methyl alcohol, ethanol, n-propyl alcohol, Virahol or their mixed solvent, preferred Virahol.
Crystal can be separated out with 0.25-12 hour, preferred 0.25-2 hour.
Crystal can be separated out under to 5 ℃ at-10 ℃ to 25 ℃, preferred-5 ℃.
In this specification sheets, " solvate " for example comprises and the solvate of organic solvent, hydrate etc.When forming solvate with organic solvent, can with the organic solvent molecule coordination of arbitrary number.When forming hydrate, can with the water molecules coordination of arbitrary number.The preferably water compound.
In this specification sheets, " general formula (I); (II); (III); (IV); (V); (VI), (VII) and the salt of the compound (VIII) " for example have: general formula (I); (II); (III); (IV); (V); (VI), (VII), compound (VIII) and basic metal (lithium, sodium, potassium etc.), alkaline-earth metal (magnesium, calcium etc.), ammonium, organic bases and amino acid whose salt, perhaps mineral acid (hydrochloric acid, Hydrogen bromide, phosphoric acid, sulfuric acid etc.), and organic acid (acetate, citric acid, toxilic acid, fumaric acid, Phenylsulfonic acid, tosic acid etc.) salt.These salt can form by the method for carrying out usually.
The crystal of the compound shown in general formula that generates among the above-mentioned preparation method (II) and the general formula (VIII) can obtain X-ray diffraction pattern by the powder X-ray X-ray analysis X.
This crystal in carrying out above-mentioned preparation process or preparation contain in the pharmaceutical composition of compound shown in the formula (VIII) as effective constituent, easily operation, therefore high purity is the crystal useful to pharmaceutical compositions.
Crystal for the compound shown in formula (II) and the formula (VIII), in aftermentioned embodiment 1-20, show X-ray diffraction pattern (X-ray diffraction condition determination: pipe ball CuK α line, tube voltage 40Kv, tube current 40mA or 50mA, dsin θ=n λ (n is an integer, d be face at interval (unit:
Figure G2007800518019D00281
), θ is diffraction angle (unit: degree))).
These crystal according to each diffraction angle or face at interval value and each tool feature.
Below provide embodiment and test example, further describe the present invention, but the present invention is not limited to this.
Use following abbreviation among the embodiment.
Me: methyl
Et: ethyl
DMF:N, dinethylformamide
THF: tetrahydrofuran (THF)
DMSO: dimethyl sulfoxide (DMSO)
TMS: tetramethylsilane
Embodiment
Synthesizing of embodiment 1 compound (II-a)
[changing 30]
Figure G2007800518019D00291
Step 1
With compound (III-a, 39.1g, 0.454mol) and compound (toluene 0.189mol) (142mL) solution dehydrates refluxed 5.5 hours for IV-a, 20.3g.With the reaction solution concentrating under reduced pressure, obtain concentrated solution.This concentrated solution is used for the reaction of back.
Step 2
(V-a, 61.3g 0.283mol), stirred 8 hours down at 120 ℃ to add compound in the concentrated solution that step 1 obtains.The concentrating under reduced pressure reaction solution, acquisition contains the concentrated solution of compound (I-a), this concentrated solution is used for the reaction of back.
Step 3
In the concentrated solution that step 2 obtains, add methyl alcohol (60mL), 24% aqueous sodium hydroxide solution (38mL), stirred 0.5 hour at 25 ℃.With the reaction solution concentrating under reduced pressure, with toluene (213mL) washing.In water layer, add 61% sulfuric acid (3.3g), add 31% sulfuric acid (26g) then, make acidity, with ethyl acetate (144mL) extraction.With the extraction liquid concentrating under reduced pressure, add 2-propyl alcohol (24mL), 0 ℃ of following partial crystallization 0.5 hour.The crystal that leaching is separated out, drying obtains compound (II-a, 36.6g, 71.4%).
Fusing point: 114 ℃
NMR (CDCl 3, TMS): 1.18 (t, 3H, J=7.7), 2.24 (s, 3H), 2.73 (q, 2H, J=7.5), 5.49 (br s, 2H), 7.09 (m, 2H), 7.29-7.38 (m, 3H), 8.38 (s, 1H), 14.53 (br s, 1H) result of powder x-ray diffraction such as tables 1 and shown in Figure 1.
The diffraction angle of main peaks: 2 θ=10.5,15.1,19.5,21.7,25.2 degree
[table 1]
Figure G2007800518019D00301
Synthesizing of embodiment 2 compounds (II-b)
[changing 31]
Figure G2007800518019D00311
Step 1
With compound (III-a, 39.1g, 0.454mol) and compound (toluene 0.189mol) (142mL) solution dehydrates refluxed 5 hours for IV-b, 23.7g.With the reaction solution concentrating under reduced pressure, obtain concentrated solution.This concentrated solution is used for the reaction of back.
Step 2
(V-a, 61.3g 0.283mol), stirred 8 hours at 117 ℃ to add compound in the concentrated solution that step 1 obtains.With the reaction solution concentrating under reduced pressure, obtain to contain the concentrated solution of compound (I-b).This concentrated solution is used for the reaction of back.
Step 3
In the concentrated solution that step 2 obtains, add methyl alcohol (60mL), 26% aqueous sodium hydroxide solution (43.7g), stirred 0.5 hour down at 25 ℃.With the reaction solution concentrating under reduced pressure, with toluene (213mL) washing.In water layer, add 61% sulfuric acid (3.3g), then add 31% sulfuric acid (26g), make acidity, with ethyl acetate (144mL) extraction.Water (95mL) washing then with the extraction liquid concentrating under reduced pressure, added 2-propyl alcohol (24mL), 0 ℃ of following partial crystallization 0.5 hour.The crystal that leaching is separated out, drying obtains compound (II-b, 35.9g, 65.6%).
Fusing point: 110-111 ℃
NMR(DMSO-d 6、TMS)：1.05(t，3H，J＝7.5)，2.24(s，3H)，2.75(q，2H，J＝7.5)，5.48(s，2H)，7.15-7.25(m，4H)，8.32(s，1H)，14.68(s，1H)
X-ray diffraction diffraction result such as table 2 and shown in Figure 2.
The diffraction angle of main peaks: 2 θ=13.7,19.0,24.2,26.4,27.8 degree
[table 2]
Figure G2007800518019D00321
Synthesizing of embodiment 3 compounds (II-c)
[changing 32]
Figure G2007800518019D00331
Step 1
With compound (III-a, 39.1g, 0.454mol) and compound (toluene 0.189mol) (142mL) solution dehydrates refluxed 5 hours for IV-c, 21.4g.With the reaction solution concentrating under reduced pressure, obtain concentrated solution.This concentrated solution is used for the reaction of back.
Step 2
(V-a, 61.3g 0.283mol), stirred 8 hours down at 117 ℃ to add compound in the concentrated solution that step 1 obtains.With the reaction solution concentrating under reduced pressure, obtain to contain the concentrated solution of compound (I-c).This concentrated solution is used for the reaction of back.
Step 3
In the concentrated solution that step 2 obtains, add methyl alcohol (60mL) and 24% aqueous sodium hydroxide solution (38.4mL), stirred 0.5 hour down at 25 ℃.With the reaction solution concentrating under reduced pressure, with toluene (213mL) washing.In water layer, add 61% sulfuric acid (3.3g), then add 31% sulfuric acid (26g), make acidity, with ethyl acetate (144mL) extraction.Water (95mL) washing with the extraction liquid concentrating under reduced pressure, added 2-propyl alcohol (24mL), 0 ℃ of partial crystallization 0.5 hour.The crystal that leaching is separated out, drying obtains compound (II-c, 37.5g, 71.5%).
Fusing point: 131 ℃
NMR(DMSO-d 6、TMS)：1.00-1.30(m，5H)，1.22(t，3H，J＝7.5)，1.55-1.90(m，6H)，2.24(s，3H)，2.82(q，2H，J＝7.2)，3.90-4.20(m，2H)，8.29(s，1H)
Powder x-ray diffraction result such as table 3 and shown in Figure 3.
The diffraction angle of main peaks: 2 θ=9.8,14.5,20.4,21.9,25.6 degree
[table 3]
Synthesizing of embodiment 4 compounds (II-d)
[changing 33]
Figure G2007800518019D00351
Step 1
With compound (III-a, 39.1g, 0.454mol), (toluene 0.189mol) (142mL) solution dehydrates refluxed 8 hours compound for IV-d, 16.5g.With the reaction solution concentrating under reduced pressure, obtain concentrated solution.This concentrated solution is used for the reaction of back.
Step 2
(V-a, 61.3g 0.283mol), stirred 8 hours down at 120 ℃ to add compound in the concentrated solution that step 1 obtains.With the reaction solution concentrating under reduced pressure, obtain to contain the concentrated solution of compound (I-d).This concentrated solution is used for the reaction of back.
Step 3
In the concentrated solution that step 2 obtains, add methyl alcohol (60mL), 24% aqueous sodium hydroxide solution (38.4mL), stirred 0.5 hour down at 25 ℃.With the reaction solution concentrating under reduced pressure, with toluene (213mL) washing.Add 61% sulfuric acid (3.3g) to water layer, then add 31% sulfuric acid (26g), make acidity.Extract with ethyl acetate (144mL).Water (95mL) washing then with the extraction liquid concentrating under reduced pressure, added 2-propyl alcohol (24mL), 0 ℃ of following partial crystallization 0.5 hour.The crystal that leaching is separated out, drying obtains compound (II-d, 28.2g, 59.3%).
Fusing point: 106 ℃
NMR (DMSO-d 6, TMS): 1.02 (d, 6H, J=6.6), 1.28 (t, 3H, J=7.5), 1.56-1.66 (m, 2H), 1.78 (m, 1H), 2.23 (s, 3H), 2.79 (q, 2H, J=7.5), 4.10-4.21 (m, 2H), 8.28 (s, 1H) powder x-ray diffraction result such as tables 4 and shown in Figure 4.
The diffraction angle of main peaks: 2 θ=10.1,10.8,21.3,26.0 degree
[table 4]
Figure G2007800518019D00361
Synthesizing of embodiment 5 compounds (II-e)
[changing 34]
Figure G2007800518019D00371
Step 1
With compound (III-a, 58.6g, 0.681mol), (toluene 0.189mol) (142mL) solution dehydrates refluxed 5 hours compound for IV-e, 27.1g.With the reaction solution concentrating under reduced pressure, obtain concentrated solution.This concentrated solution is used for the reaction of back.
Step 2
(V-a, 61.3g 0.283mol), stirred 8 hours down at 117 ℃ to add compound in the concentrated solution that step 1 obtains.With the reaction solution concentrating under reduced pressure, obtain to contain the concentrated solution of compound (I-e).This concentrated solution is used for the reaction of back.
Step 3
In the concentrated solution that step 2 obtains, add methyl alcohol (59mL), 24% aqueous sodium hydroxide solution (38.6mL), stirred 0.5 hour down at 25 ℃.With the reaction solution concentrating under reduced pressure, with toluene (212mL) washing.In water layer, add 61% sulfuric acid (3.3g), then add 31% sulfuric acid (26g), make acidity.Extract with ethyl acetate (144mL).Water (95mL) washing then with the extraction liquid concentrating under reduced pressure, added 2-propyl alcohol (24mL), 0 ℃ of following partial crystallization 0.5 hour.The crystal that leaching is separated out, drying obtains compound (II-e, 39.6g, 68.1%).
Fusing point: 131-132 ℃
1H-NMR (CDCl 3, TMS): 1.21 (t, 3H, J=7.7), 2.25 (s, 3H), 2.73 (q, 2H, J=7.4), 5.42 (br s, 2H), 6.86 (m, 1H), 6.96 (ddd, 1H, J=10.8,7.4 and 2.3), (7.15 J=9.9and 8.3 for dt, 1H), 8.39 (s, 1H), 14.31 (br s, 1H)
Powder x-ray diffraction result such as table 5 and shown in Figure 5.
The diffraction angle of main peaks: 2 θ=13.4,13.8,19.0,24.3,27.9 degree
[table 5]
Figure G2007800518019D00381
Synthesizing of embodiment 6 compounds (II-f)
[changing 35]
Figure G2007800518019D00391
Step 1
With compound (III-b, 10.0g, 0.079mol), (toluene 0.079mol) (100mL) solution dehydrates refluxed 7 hours compound for IV-c, 8.97g.
Step 2
In the reaction solution that step 1 obtains, add compound (V-b, 20.56g, 0.095mol), reflux 16 hours.With the reaction solution concentrating under reduced pressure, obtain to contain the concentrated solution of compound (I-f).This concentrated solution is used for the reaction of back.
Step 3
In the concentrated solution that step 2 obtains, add methyl alcohol (150mL), (79mL 0.158mol), stirred 3 hours down at 25 ℃ the 2N aqueous sodium hydroxide solution.With the reaction solution concentrating under reduced pressure, add toluene and water, separate water layer.In water layer, add 5N hydrochloric acid (34mL), use ethyl acetate extraction.With the extraction liquid concentrating under reduced pressure, add 2-propyl alcohol (40mL), stirred partial crystallization 1 hour down at 0 ℃.The crystal that leaching is separated out, drying obtains compound (II-f, 15.5g, 61.6%).
NMR(CDCl 3、TMS)：1.05-1.71(m，19H)，2.70-2.74(m，2H)，2.98-3.01(m，2H)，4.06(bs，2H)，8.21(s，1H)，14.96(s，1H)
Powder x-ray diffraction result such as table 6 are shown in Figure 6.
The diffraction angle of main peaks: 2 θ=10.2,11.4,15.0,18.2,20.6,21.5 degree
[table 6]
??20 The d value Intensity Relative intensity
??10.225 ??8.64424 ??75.6 ??68.3
??11.368 ??7.777 ??72.3 ??65.4
??14.963 ??5.91599 ??70.3 ??63.5
??15.34 ??5.7713 ??32.9 ??29.7
??15.857 ??5.58444 ??21.2 ??19.2
??17.052 ??5.19562 ??34.5 ??31.2
??18.15 ??4.88349 ??72.3 ??65.4
??18.713 ??4.73784 ??15 ??13.6
??19.73 ??4.49593 ??26.2 ??23.7
??20.074 ??4.41965 ??42.2 ??38.1
??20.565 ??4.31529 ??111 ??100
??21.196 ??4.18823 ??43.8 ??39.6
??21.466 ??4.13617 ??83.3 ??75.3
??21.975 ??4.04138 ??27.9 ??25.2
??22.823 ??3.89325 ??62.6 ??56.6
??23.408 ??3.79726 ??50.8 ??45.9
??23.748 ??3.74359 ??49.8 ??45.1
??24.105 ??3.68889 ??26.5 ??24
??26.736 ??3.33161 ??14.3 ??13
??28.598 ??3.11872 ??12.4 ??11.2
??28.892 ??3.08773 ??11.8 ??10.7
??29.557 ??3.01971 ??13.5 ??12.2
??29.82 ??2.99372 ??13 ??11.7
??31.52 ??2.83599 ??16.1 ??14.6
??33.017 ??2.71078 ??11.3 ??10.2
??33.454 ??2.67632 ??9.61 ??8.7
??34.817 ??2.57465 ??8.55 ??7.7
??35.301 ??2.54042 ??8.78 ??7.9
??35.937 ??2.49694 ??8.51 ??7.7
??36.337 ??2.47034 ??6.89 ??6.2
??37.262 ??2.4111 ??6.34 ??5.7
??38.3 ??2.34809 ??7.61 ??6.9
Synthesizing of embodiment 7 compounds (II-g)
[changing 36]
Figure G2007800518019D00411
Step 1
With compound (III-b, 30.0g, 0.238mol), (toluene 0.286mol) (80mL) solution dehydrates refluxed 5.5 hours compound for IV-f, 20.9g.
Step 2
In the reaction solution that step 1 obtains, add compound (V-b, 51.5g, 0.238mol), reflux 2 hours.With the reaction solution concentrating under reduced pressure, obtain to contain the concentrated solution of compound (I-g).This concentrated solution is used for the reaction of back.
Step 3
In the concentrated solution that step 2 obtains, add methyl alcohol (200mL), tetrahydrofuran (THF) (200mL), 2 Equivalent Hydrogen aqueous solution of sodium oxide (149mL), reaction finishes the back and carries out same operation with embodiment 1, in the crystallinity concentration residue that obtains, add methyl alcohol (200mL), carry out recrystallization.The crystal that leaching is separated out, drying obtains compound (II-g, 47.9g, 72.5%).
NMR(DMSO-d 6、TMS)：1.00(t，3H，J＝7.5)，1.35-1.55(m，6H)，1.60-1.86(m，6H)，2.63-2.71(m，2H)，2.90-2.99(m，2H)，3.99-4.21(m，2H)，8.27(s，1H)，14.78(br?s，1H)
Powder x-ray diffraction result such as table 7 and shown in Figure 7.
The diffraction angle of main peaks: 2 θ=9.2,9.7,10.0,15.5,19.7 degree
[table 7]
??2θ The d value Intensity Relative intensity
??9.157 ??9.64983 ??515 ??100
??9.74 ??9.0733 ??82.4 ??16
??9.998 ??8.83963 ??165 ??32
??10.701 ??8.26016 ??16.5 ??3.2
??14.051 ??6.29757 ??24.7 ??4.8
??15.129 ??5.8512 ??37.9 ??7.4
??15.504 ??5.71047 ??77.8 ??15.1
??16.271 ??5.44302 ??20.2 ??3.9
??17.419 ??5.08702 ??8.46 ??1.6
??18.146 ??4.88461 ??43.7 ??8.5
??18.432 ??4.80948 ??32.7 ??6.4
??18.749 ??4.7289 ??25.2 ??4.9
??19.4 ??4.57168 ??41.5 ??8
??19.66 ??4.51179 ??80.8 ??15.7
??20.188 ??4.39506 ??33.8 ??6.6
??20.53 ??4.32258 ??47.7 ??9.3
??21.466 ??4.13612 ??77.1 ??15
??22.073 ??4.02376 ??22.6 ??4.4
??22.349 ??3.97472 ??20.2 ??3.9
??22.882 ??3.88329 ??10.6 ??2.1
??23.449 ??3.79069 ??23.4 ??4.5
??24.491 ??3.63169 ??29 ??5.6
??24.807 ??3.5861 ??27.9 ??5.4
??25.1 ??3.54492 ??16.3 ??3.2
??26.069 ??3.41533 ??18 ??3.5
??26.504 ??3.3602 ??12.2 ??2.4
??27.549 ??3.23514 ??8.93 ??1.7
??28.49 ??3.13036 ??11.8 ??2.3
??28.914 ??3.08543 ??17.5 ??3.4
??29.707 ??3.00485 ??13.6 ??2.6
??30.226 ??2.95439 ??13.9 ??2.7
??30.66 ??2.91355 ??14.9 ??2.9
??30.92 ??2.88962 ??35.6 ??6.9
??31.382 ??2.84813 ??8.82 ??1.7
??31.978 ??2.79642 ??18.2 ??3.5
??32.236 ??2.77461 ??14.7 ??2.9
??32.916 ??2.71881 ??7.92 ??1.5
??34.088 ??2.62797 ??7.28 ??1.4
??34.783 ??2.57704 ??9.52 ??1.8
??35.37 ??2.53563 ??10.3 ??2
??36.075 ??2.48769 ??6.57 ??1.3
??38.451 ??2.33925 ??8.15 ??1.6
??38.959 ??2.30987 ??6.79 ??1.3
Synthesizing of embodiment 8 compounds (II-h)
[changing 37]
Step 1
With compound (III-b, 10.0g, 0.079mol), (toluene 0.095mol) (100mL) solution dehydrates refluxed 7 hours compound for IV-b, 11.9g.
Step 2
In the reaction solution that step 1 obtains, add compound (V-b, 23.99g, 0.111mol), reflux 15 hours.With the reaction solution concentrating under reduced pressure, obtain to contain the concentrated solution of compound (I-h).This concentrated solution is used for the reaction of back.
Step 3
In the concentrated solution that step 2 obtains, add methyl alcohol (150mL), (79mL 0.158mol), stirred 2 hours down at 25 ℃ the 2N aqueous sodium hydroxide solution.With the reaction solution concentrating under reduced pressure, add toluene and water, separate water layer.In water layer, add 2-propyl alcohol (35mL), 34mL 5 equivalent hydrochloric acid, stirred partial crystallization 1 hour down at 25 ℃.The crystal that leaching is separated out, drying obtains compound (II-h, 19.8g, 76.0%).
NMR(DMSO-d 6、TMS)：1.20-1.45(m，4H)，1.55-1.63(m，4H)，2.70-2.80(m，2H)，2.85-2.95(m，2H)，5.47(s，2H)，7.18(d，4H，J＝8.1)，8.29(s，1H)，14.7(s，1H)
Powder x-ray diffraction result such as table 8 and shown in Figure 1.
The diffraction angle of main peaks: 2 θ=13.2,18.7,19.5,20.0,22.7 degree
[table 8]
??2θ The d value Intensity Relative intensity
??7.566 ??11.67471 ??15 ??9.6
??10.77 ??8.20772 ??15.4 ??9.9
??12.192 ??7.25359 ??41.7 ??26.7
??13.203 ??6.70005 ??84.9 ??54.4
??14.048 ??6.29902 ??25.7 ??16.4
??14.683 ??6.02792 ??7.87 ??5
??15.147 ??5.8443 ??48.2 ??30.8
??17.193 ??5.15322 ??39 ??24.9
??17.799 ??4.97912 ??11.3 ??7.2
??18.657 ??4.75212 ??136 ??86.8
??19.469 ??4.55556 ??101 ??64.7
??20.022 ??4.43099 ??156 ??100
??21.775 ??4.0781 ??33.4 ??21.4
??22.332 ??3.97759 ??18.2 ??11.6
??22.707 ??3.91287 ??96.4 ??61.7
??23.972 ??3.70907 ??37.4 ??23.9
??24.275 ??3.66343 ??45.2 ??28.9
??25.153 ??3.5375 ??34.9 ??22.3
??25.995 ??3.42484 ??32.8 ??21
??26.297 ??3.38625 ??14.7 ??9.4
??26.62 ??3.34582 ??11.4 ??7.3
??27.171 ??3.27922 ??14.4 ??9.2
??28.373 ??3.14302 ??9.63 ??6.2
??28.98 ??3.07852 ??10.4 ??6.7
??29.205 ??3.05527 ??13.4 ??8.6
??30.55 ??2.92382 ??8.97 ??5.7
??30.839 ??2.89702 ??14.1 ??9
??31.677 ??2.82234 ??14.7 ??9.4
??32.168 ??2.78033 ??9.8 ??6.3
??32.465 ??2.75559 ??15.4 ??9.8
??32.75 ??2.7322 ??8.08 ??5.2
??33.771 ??2.6519 ??8.76 ??5.6
??34.306 ??2.6118 ??13.7 ??8.8
??34.966 ??2.56396 ??13.7 ??8.8
??36.025 ??2.49102 ??17 ??10.9
??39.509 ??2.27902 ??16.6 ??10.6
Synthesizing of embodiment 9 compounds (II-i)
[changing 38]
Figure G2007800518019D00451
Step 1
With compound (III-b, 10.1g, 0.0800mol), (toluene 0.0800mol) (100mL) solution dehydrates refluxed 6 hours compound for IV-d, 6.98g.
Step 2
The reaction solution that obtains to step 1 add compound (V-b, 20.8g, 0.0960mol), reflux 15 hours.With the reaction solution concentrating under reduced pressure, obtain to contain the concentrated solution of compound (I-i).This concentrated solution is used for the reaction of back.
Step 3
In the concentrated solution that step 2 obtains, add methyl alcohol (86mL) and tetrahydrofuran (THF) (86mL), 2N aqueous sodium hydroxide solution (80.0mL), stirred 3 hours down at 25 ℃.With the reaction solution concentrating under reduced pressure, add toluene and water, separate water layer.The water layer that obtains is joined in the mixing solutions of 5N hydrochloric acid (40mL) and ethyl acetate (300mL), with ethyl acetate (50mL) extraction.With the extraction liquid concentrating under reduced pressure, add 2-propyl alcohol (8mL), stirred partial crystallization 15 hours down at 25 ℃.The crystal that leaching is separated out, drying obtains compound (II-i, 12.1g, 52.0%).
NMR(DMSO-d 6)：0.95(d，6H，J＝6.6)，1.33(brs，2H)，1.43(brs，2H)，1.50-1.60(m，4H)，1.71-1.78(m，3H)，2.70(m，2H)，2.97(m，2H)，4.14(m，2H)，8.19(s，1H)，14.9(s，1H)
Powder x-ray diffraction result such as table 9 and shown in Figure 9.
The diffraction angle of main peaks: 2 θ=8.4,9.8,14.3,20.3,21.8 degree
[table 9]
??2θ The d value Intensity Relative intensity
??8.353 ??10.57689 ??232 ??100
??9.833 ??8.98789 ??211 ??90.9
??13.02 ??6.79412 ??6.61 ??2.9
??13.585 ??6.51263 ??9.94 ??4.3
??14.328 ??6.17642 ??96.4 ??41.6
??15.338 ??5.77198 ??25.4 ??11
??15.666 ??5.65203 ??51.9 ??22.4
??16.078 ??5.50794 ??12.6 ??5.4
??16.586 ??5.34029 ??35.5 ??15.3
??17.345 ??5.10841 ??29.8 ??12.9
??19.34 ??4.58573 ??63.5 ??27.4
??19.572 ??4.532 ??114 ??49.4
??20.319 ??4.36688 ??71.5 ??30.9
??20.668 ??4.29392 ??20.5 ??8.8
??21.371 ??4.15431 ??24.4 ??10.5
??21.771 ??4.0789 ??71.3 ??30.8
??22.525 ??3.94392 ??15.7 ??6.8
??23.241 ??3.82401 ??19 ??8.2
??24.12 ??3.68663 ??67.3 ??29.1
??24.791 ??3.58837 ??38.5 ??16.6
??25.156 ??3.53711 ??10.5 ??4.6
??25.8 ??3.45029 ??8.02 ??3.5
??27.238 ??3.2713 ??8.36 ??3.6
??28.016 ??3.18219 ??10.3 ??4.5
??29.022 ??3.07416 ??42.1 ??18.2
??29.417 ??3.03379 ??10.4 ??4.5
??29.859 ??2.98982 ??19.3 ??8.4
??30.463 ??2.93195 ??15 ??6.5
??30.925 ??2.88921 ??9.75 ??4.2
??31.742 ??2.81665 ??9.82 ??4.2
??32.534 ??2.74985 ??10.1 ??4.4
??32.892 ??2.72077 ??13.8 ??5.9
??33.51 ??2.67202 ??7.83 ??3.4
??34.2 ??2.61964 ??9.04 ??3.9
??34.484 ??2.59868 ??8.55 ??3.7
??35.75 ??2.50956 ??8.67 ??3.7
??36.751 ??2.44343 ??8.08 ??3.5
??37.722 ??2.38277 ??11.8 ??5.1
??39.205 ??2.29599 ??9.1 ??3.9
??39.765 ??2.26492 ??7.78 ??3.4
Synthesizing of embodiment 10 compounds (II-j)
[changing 39]
Figure G2007800518019D00471
Step 1
With compound (III-b, 10.6g, 0.084mol), (toluene 0.070mol) (80mL) solution dehydrates refluxed 7 hours compound for IV-e, 10.0g.
Step 2
In the reaction solution that step 1 obtains, add compound (V-b, 15.9g, 0.074mol), reflux 7 hours.With the reaction solution concentrating under reduced pressure, obtain to contain the concentrated solution of compound (I-j), this concentrated solution is used for the reaction of back.
Step 3
In the concentrated solution that step 2 obtains, add water (40mL) solution of methyl alcohol (70mL), sodium hydroxide (8.38g), at room temperature stirred 1 hour.After reaction finishes, carry out operation similarly to Example 1, in the crystallinity concentration residue that obtains, add methyl alcohol (100mL), be concentrated into 50g, leave standstill under 0 ℃.The crystal that leaching is separated out, with a spot of cold methanol washing, drying obtains compound (II-j, 12.5g, 51.7%).
NMR(DMSO-d 6、TMS)：1.37-1.55(m，4H)，1.65-1.80(m，4H)，2.64-2.72(m，2H)，2.82-2.91(m，2H)，5.42(s，2H)，6.85(m，1H)，6.95(m，1H)，7.15(m，1H)，8.38(s，1H)，14.34(br?s，1H)
Powder x-ray diffraction result such as table 10 and shown in Figure 10.
The diffraction angle of main peaks: 2 θ=14.6,15.7,17.9,23.5,26.8,27.7 degree
[table 10]
??2θ The d value Intensity Relative intensity
??8.874 ??9.95659 ??8.86 ??1.2
??9.756 ??9.05824 ??32.6 ??4.3
??10.305 ??8.57703 ??47.9 ??6.4
??11.144 ??7.93334 ??51.1 ??6.8
??12.553 ??7.04558 ??28.5 ??3.8
??12.919 ??6.84683 ??9.64 ??1.3
??13.851 ??6.38822 ??13.2 ??1.8
??14.621 ??6.05345 ??134 ??17.8
??15.313 ??5.78145 ??41.5 ??5.5
??15.731 ??5.62873 ??148 ??19.7
??17.352 ??5.10646 ??90.8 ??12.1
??17.9 ??4.95135 ??751 ??100
??19.655 ??4.51293 ??27.7 ??3.7
??20.749 ??4.27748 ??58.3 ??7.8
??21.418 ??4.14532 ??13.1 ??1.7
??21.857 ??4.06297 ??87.7 ??11.7
??22.607 ??3.92993 ??14.1 ??1.9
??23.513 ??3.78048 ??216 ??28.8
??24.278 ??3.66308 ??116 ??15.4
??25.212 ??3.52939 ??8.67 ??1.2
??25.957 ??3.42984 ??14 ??1.9
??26.267 ??3.39 ??20 ??2.7
??26.794 ??3.32453 ??128 ??17.1
??27.652 ??3.22326 ??160 ??21.3
??27.965 ??3.18785 ??57.8 ??7.7
??28.673 ??3.11081 ??15 ??2
??29.929 ??2.98303 ??29.2 ??3.9
??30.87 ??2.89423 ??9.3 ??1.2
??31.709 ??2.81953 ??47.4 ??6.3
??32.895 ??2.72054 ??10.5 ??1.4
??34.761 ??2.57864 ??21.3 ??2.8
??35.43 ??2.53147 ??21.3 ??2.8
??35.996 ??2.49297 ??9.23 ??1.2
??37.007 ??2.42715 ??10.1 ??1.3
??37.632 ??2.38823 ??7.93 ??1.1
??38.335 ??2.34608 ??9.16 ??1.2
??39.15 ??2.29909 ??8.46 ??1.1
Synthesizing of embodiment 11 compounds (VIII-a)
[changing 40]
Figure G2007800518019D00491
Step 1
Compound (II-b to embodiment 2 acquisitions, 7.35g, 25.4mmol), add in the solution of toluene (8.7mL) and N-methylpyridone (8.7mL) thionyl chloride (3.32g, 27.9mmol), stirred 0.5 hour down at 25 ℃, obtain to contain the reaction solution of compound (VI-a).This reaction solution is used for the reaction of back.
Step 2
In the reaction solution that step 1 obtains, add compound (VII-a, 5.90g, 30.5mmol) and triethylamine (3.1g, the solution of toluene 30.5mmol) (18.5mL), N-methylpyridone (18.5mL).(5.66g 55.9mmol), stirred 0.5 hour down at 25 ℃ then, obtained to contain the reaction solution of compound (IX-a) then to add triethylamine.With 6% sulfuric acid (34.6g), 4% sodium hydroxide (32.2g), pure water (14.5mL) washing, concentrating under reduced pressure then.This concentrated solution is used for the reaction of back.
Step 3
In the concentrated solution that step 2 obtains, add methyl alcohol (25.9mL), 36% aqueous sodium hydroxide solution (7.06g), stirred 4 hours down at 50 ℃.With the reaction solution concentrating under reduced pressure, add 2-propyl alcohol (54.6g), 10% sulfuric acid (68.5g), make acidity, 25 ℃ of following partial crystallizations 0.3 hour.The crystal that leaching is separated out, drying obtains compound (VIII-a, 9.78g, 92.9%).
Fusing point: 237-238 ℃
NMR (DMSO-d 6, TMS): 1.05 (t, 3H, J=7.8Hz), 1.15-2.10 (m, 10H), 2.19 (s, 3H), 2.67 (dd, 2H, J=7.2 and 15Hz), 5.42 (s, 2H), 7.13-7.22 (m, 4H), 8.19 (s, 1H), 10.14 (s, 1H), 12.17 (br, 1H)
Powder x-ray diffraction result such as table 11 and shown in Figure 11.
The diffraction angle of main peaks: 2 θ=9.4,17.8,18.5,20.9,38.4 degree
[table 11]
Synthesizing of embodiment 12 compounds (VIII-b)
[changing 41]
Figure G2007800518019D00511
Step 1
The compound that obtains at embodiment 2 (II-b, 7.36g, 25.4mmol), (3.3g 27.9mmol), stirred 0.5 hour down at 25 ℃, obtained to contain the reaction solution of compound (VI-a) to add thionyl chloride among the DMF (1.0mL), THF (73.6mL) solution.This reaction solution is used for the reaction of back.
Step 2
In the reaction solution that step 1 obtains, add compound (VII-b, 5.85g, 27.9mmol), pyridine (20.1g, 254mmol), (620mg 5.1mmol), stirred 20 hours down at 25 ℃ dimethyl aminopyridine, added 14% hydrochloric acid (134.6g) then.Extract with ethyl acetate (217mL).With extraction liquid water (74mL), 5% sodium bicarbonate water (74mL) washing.With the extraction liquid concentrating under reduced pressure, obtain to contain the concentrated solution of compound (IX-b).This concentrated solution is used for the reaction of back.
Step 3
In the concentrated solution that step 2 obtains, add THF (35.7mL), methyl alcohol (25.5mL), 1 Equivalent Hydrogen aqueous solution of sodium oxide (45.9mL), stirred 2 hours down at 0 ℃.Add 2 equivalent hydrochloric acid (25.2mL), make acidity, add entry (40mL), then 0 ℃ of following partial crystallization 0.5 hour.The crystal that leaching is separated out, drying obtains compound (VIII-b, 9.04g, 91.7%).
Fusing point: 202-203 ℃
NMR(DMSO-d 6、TMS)：1.06(t，3H，J＝7.5Hz)，2.24(s，3H)，2.75(q，2H，J＝7.5Hz)，3.79(s，2H)，5.49(br-s，2H)，7.13-7.28(m，4H)，8.42(s，1H)，13.65(s，1H)
Powder x-ray diffraction result such as table 12 and shown in Figure 12.
The diffraction angle of main peaks: 2 θ=8.5,18.4,23.9,25.2 degree
[table 12]
Figure G2007800518019D00521
Synthesizing of embodiment 13 compounds (VIII-c)
[changing 42]
Figure G2007800518019D00531
Step 1
Compound (II-d to embodiment 4 acquisitions, 6.38g, 25.4mmol), add in the solution of toluene (10.7mL), N-methylpyridone (10.7mL) thionyl chloride (3.32g, 27.9mmol), stirred 0.5 hour down at 25 ℃, obtain to contain the reaction solution of compound (VI-d).This reaction solution is used for the reaction of back.
Step 2
In the reaction solution that step 1 obtains, add compound (VII-a, 5.41g, 27.9mmol) and triethylamine (2.83g, the solution of toluene 27.9mmol) (15.9mL), N-methylpyridone (15.9mL).(5.66g 55.9mmol), stirred 1 hour down at 25 ℃ then, obtained to contain the reaction solution of compound (IX-c) then to add triethylamine.With 6% sulfuric acid (30.3g), 4% sodium hydroxide (28.3g), water (12.6mL) washing, concentrating under reduced pressure then.This concentrated solution is used for the reaction of back.
Step 3
In the concentrated solution that step 2 obtains, add methyl alcohol (22.7mL), 36% aqueous sodium hydroxide solution (7.06g), stirred 4 hours down at 50 ℃.With the reaction solution concentrating under reduced pressure, add 2-propyl alcohol (60.3mL), 10% sulfuric acid (68.5g), make acidity, 0 ℃ of following partial crystallization 1.5 hours.The crystal that leaching is separated out, drying obtains compound (VIII-d, 7.77g, 81.3%).
Fusing point: 170-171 ℃
NMR(DMSO-d 6、TMS)：0.97(d，6H，J＝6.6)，1.18(s，3H，J＝7.5)，1.26-1.78(m，8H)，2.16(s，3H)，2.75(q，2H，J＝7.5)，4.09(m，2H)，8.09(s，1H)，10.24(s，3H)
Powder x-ray diffraction result such as table 13 and shown in Figure 13.
The diffraction angle of main peaks: 2 θ=10.9,13.3,20.4,22.7 degree
[table 13]
Figure G2007800518019D00541
Synthesizing of embodiment 14 compounds (VIII-d)
[changing 43]
Figure G2007800518019D00551
Step 1
Compound (II-e to embodiment 5 acquisitions, 7.81g, 25.4mmol), add in the solution of toluene (18mL), N-methylpyridone (18mL) thionyl chloride (3.33g, 28.0mmol), stirred 0.5 hour down at 25 ℃, obtain to contain the reaction solution of compound (VI-c).This reaction solution is used for the reaction of back.
Step 2
The reaction solution that obtains to step 1 adds compound (VII-c, 6.20g, 28.0mmol), toluene (10.8mL), N-methylpyridone (10.8mL), triethylamine (8.49g, 83.9mmol), stirred 0.5 hour down at 25 ℃, obtain to contain compound (IX-e) reaction solution.With 6% sulfuric acid (37.3g), 4% sodium hydroxide (33.7g), water (15.6mL) washing, concentrating under reduced pressure then.This concentrated solution is used for the reaction of back.
Step 3
In the concentrated solution that step 2 obtains, add THF (42mL), methyl alcohol (30mL), 1 Equivalent Hydrogen aqueous solution of sodium oxide (50.8mL), stirred 3 hours down at 50 ℃.Add 2 equivalent hydrochloric acid (25.4mL), make acidity, add entry (24mL), 0 ℃ of following partial crystallization 0.3 hour.The crystal that leaching is separated out, drying obtains compound (VIII-d, 10.6g, 90.7%).
Fusing point: 194-195 ℃
NMR(DMSO-d 6、TMS)：1.04(t，3H，J＝7.5)，1.22-1.58(m，10H)，2.17(s，2H)，2.18(s，3H)，2.65(q，2H，J＝7.5)，3.40(d，2H，J＝6.3)，5.43(brs，2H)，7.11-7.21(m，4H)，8.25(s，1H)，9.94(t，1H，J＝5.7)，12.15(brs，1H)
Powder x-ray diffraction is table 14 and shown in Figure 14 as a result.
The diffraction angle of main peaks: 2 θ=4.7,12.8,15.8,17.5,24.3,25.7 degree
[table 14]
Figure G2007800518019D00561
Synthesizing of embodiment 15 compounds (VIII-e)
[changing 44]
Figure G2007800518019D00571
Step 1
Compound (II-f to embodiment 6 acquisitions, 800mg, 2.52mmol), add in the solution of tetrahydrofuran (THF) (8mL) oxalyl chloride (352mg, 2.77mmol) and dimethyl formamide (2), stirred 1 hour down at 25 ℃, obtain to contain the reaction solution of compound (VI-d).This reaction solution is used for the reaction of back.
Step 2
In the reaction solution that step 1 obtains, add compound (VII-d, 516mg, 2.77mmol) and triethylamine (0.798g, 7.89mmol).Stirred 2 hours down at 25 ℃, obtain to contain the reaction solution of compound (IX-e).Add dilute hydrochloric acid, use ethyl acetate extraction, with saturated sodium bicarbonate water, pure water (14.5mL) washing, concentrating under reduced pressure then.Resistates with acetone-hexane recrystallization, is obtained IX-e (577mg, 47%).
Step 3
(350mg, 0.72mmol) (2.2mL 2.2mmol), at room temperature stirred 2 hours the IX-e that obtains to step 2 for middle adding methyl alcohol (3mL), tetrahydrofuran (THF) (3mL) and 1 Equivalent Hydrogen aqueous solution of sodium oxide.Add dilute hydrochloric acid, make acidity, use ethyl acetate extraction, washing.Concentrate organic layer, with resistates acetone-hexane recrystallization, the crystal that leaching is separated out, drying obtains compound (VIII-e, 370mg, 80.9%).
NMR(CDCl 3、TMS)：1.00-1.90(m，19H)，2.62-2.73(m，2H)，2.90-3.00(m，2H)，3.90-4.20(br，2H)，5.68(br，1H)，7.46(br，1H)，8.35(s，1H)，8.91(s，1H)，13.64(s，1H)
Powder x-ray diffraction result such as table 15 and shown in Figure 15.
The diffraction angle of main peaks: 2 θ=6.9,14.0,19.4,21.6 degree
[table 15]
??2θ The d value Intensity Relative intensity
??6.949 ??12.71033 ??69.4 ??100
??9.383 ??9.4175 ??19.8 ??28.6
??9.976 ??8.85919 ??6.77 ??9.8
??10.494 ??8.42308 ??6.46 ??9.3
??10.842 ??8.15343 ??13.2 ??19
??11.195 ??7.89695 ??7.49 ??10.8
??11.687 ??7.56596 ??13 ??18.8
??12.927 ??6.84278 ??10.8 ??15.6
??13.652 ??6.48101 ??7.87 ??11.3
??13.984 ??6.32766 ??51.8 ??74.6
??15.096 ??5.86399 ??23.7 ??34.1
??15.575 ??5.68475 ??10.9 ??15.8
??16.531 ??5.35819 ??19 ??27.4
??16.903 ??5.24084 ??7.62 ??11
??17.856 ??4.96333 ??24.1 ??34.7
??18.43 ??4.81014 ??30.6 ??44.1
??19.354 ??4.58237 ??64.3 ??92.7
??19.995 ??4.43699 ??9.79 ??14.1
??20.529 ??4.32276 ??32.5 ??46.9
??21.057 ??4.21553 ??16.5 ??23.8
??21.594 ??4.11181 ??48.7 ??70.2
??21.78 ??4.07719 ??35.5 ??51.2
??22.495 ??3.94922 ??23.1 ??33.2
??23.35 ??3.80645 ??11.1 ??16.1
??25.334 ??3.51274 ??12.3 ??17.7
??26.345 ??3.38018 ??15.9 ??22.9
??27.262 ??3.26852 ??7.63 ??11
??27.908 ??3.19429 ??10.3 ??14.9
??28.811 ??3.09624 ??11.6 ??16.8
??29.656 ??3.00984 ??8.7 ??12.5
??31.556 ??2.8328 ??11.9 ??17.1
??32.193 ??2.77826 ??6.21 ??8.9
??32.632 ??2.74186 ??6.26 ??9
??33.814 ??2.64866 ??7.25 ??10.4
??34.344 ??2.60901 ??8.31 ??12
??35.005 ??2.56119 ??6.12 ??8.8
??36.622 ??2.45176 ??7.11 ??10.2
??37.24 ??2.41248 ??6.2 ??8.9
??38.748 ??2.32197 ??10.3 ??14.8
Synthesizing of embodiment 16 compounds (VIII-f)
[changing 45]
Figure G2007800518019D00591
Step 1
((300mg 2.53mmol) and DMF (2), stirred 0.5 hour down at 25 ℃ the compound that obtains to embodiment 6, and acquisition contains the reaction solution of compound (VI-d) to add thionyl chloride in THF 2.30mmol) (3.5mL) suspension for II-f, 0.73g.This reaction solution is used for the reaction of back.
Step 2
Ice-cooled down, the reaction solution that step 1 is obtained slowly be added drop-wise to compound (VII-e, 529mg, 2.53mmol), (815mg is 8.05mmol) and in tetrahydrofuran (THF) (4mL) solution, 25 ℃ of stirrings 1.5 hours down for triethylamine.Add dilute hydrochloric acid, use ethyl acetate extraction.With extraction liquid water, 5% sodium bicarbonate water washing.With the extraction liquid concentrating under reduced pressure, in the gained resistates, add methyl alcohol, obtain compound (IX-f, 832mg, 74.2%).
Step 3
(1.71mmol) middle THF (2mL), methyl alcohol (1.5mL), the 1 Equivalent Hydrogen aqueous solution of sodium oxide (2.5mL) of adding at room temperature stirred 3 hours the compound that obtains to step 2 for IX-f, 832mg.In reaction solution, add toluene and water, separate water layer.Add dilute hydrochloric acid to isolating water layer, make acidity, the crystal that leaching generates, drying, the acquisition target compound (VIII-f, 838mg, quantitatively).
NMR(DMSO-d 6、TMS)：1.04-1.88(m，19H)，2.60(t，2H，J＝7.5)，2.71(t-like，2H)，2.84(t，2H，J＝7.5)，3.00(t-like，2H)，4.07(brd，2H)，6.86(s，1H)，8.28(s，1H)，12，15(br，1H)，13.43(s，1H)
Powder x-ray diffraction result such as table 16 and shown in Figure 16.
The diffraction angle of main peaks: 2 θ=12.9,19.9,20.4,21.2 degree
[table 16]
??2θ The d value Intensity Relative intensity
??8.852 ??9.98183 ??17.6 ??16.8
??1.0.352 ??8.53796 ??10.8 ??10.3
??11.18 ??7.90788 ??12.8 ??12.2
??11.557 ??7.65022 ??24 ??23
??1.2.378 ??7.14502 ??17.7 ??16.9
??12.896 ??6.8589 ??54.7 ??52.3
??13.529 ??6.53961 ??28.1 ??26.8
??14.554 ??6.08113 ??26.1 ??24.9
??14.937 ??5.92591 ??8.7 ??8.3
??16.278 ??5.44072 ??19.6 ??18.7
??17.059 ??5.19342 ??48.5 ??46.3
??17.7 ??5.00682 ??21.4 ??20.4
??18.735 ??4.73242 ??15.1 ??14.4
??19.018 ??4.66255 ??21.2 ??20.2
??19.937 ??4.44975 ??68.6 ??65.5
??20.441 ??4.34118 ??105 ??100
??20.764 ??4.27442 ??40.4 ??38.6
??21.224 ??4.18275 ??54.3 ??51.8
??21.855 ??4.06333 ??37.1 ??35.4
??22.324 ??3.97903 ??12 ??11.4
??23.186 ??3.833 ??31.8 ??30.4
??24.18 ??3.6776 ??21.4 ??20.4
??24.815 ??3.58502 ??17.9 ??17
??26.771 ??3.32733 ??9.96 ??9.5
??27.751 ??3.21199 ??9.41 ??9
??28.115 ??3.17129 ??7.64 ??7.3
??28.69 ??3.109 ??9.85 ??9.4
??29.415 ??3.03399 ??11.2 ??10.7
??31.776 ??2.81376 ??8.94 ??8.5
??32.046 ??2.79062 ??8.99 ??8.6
??32.698 ??2.73647 ??7.7 ??7.4
??34.257 ??2.61544 ??6.36 ??6.1
??36.77 ??2.44222 ??6.31 ??6
??37.503 ??2.39615 ??6.75 ??6.4
??38.905 ??2.31298 ??7.03 ??6.7
??39.776 ??2.26429 ??8.36 ??8
Synthesizing of embodiment 17 compounds (VIII-g)
[changing 46]
Figure G2007800518019D00611
Step 1
((410mg 3.45mmol) and DMF (2), stirred 0.5 hour down at 25 ℃ the compound that obtains to embodiment 6, and acquisition contains the reaction solution of compound (VI-d) to add thionyl chloride in THF 3.15mmol) (5mL) suspension for II-f, 1.00g.This reaction solution is used for the reaction of back.
Step 2
The reaction solution that step 1 is obtained slowly be added drop-wise to compound (VII-f, 786mg, 4.76mmol), (958mg 9.47mmol) and in tetrahydrofuran (THF) (5mL) solution, 25 ℃ of stirrings 1.5 hours down, adds dilute hydrochloric acid to triethylamine then, uses ethyl acetate extraction.With extraction liquid water, 5% sodium bicarbonate water washing.With the extraction liquid concentrating under reduced pressure, obtain to contain the resistates (1.57g) of compound (IX-g).This resistates is used for the reaction of back.
Step 3
In the resistates (1.57g) that step 2 obtains, add THF (7.8mL), methyl alcohol (7.8mL), 2 Equivalent Hydrogen aqueous solution of sodium oxide (4.73mL), at room temperature stirred 1.5 hours.Add toluene and water to reaction solution, separate water layer.Add dilute hydrochloric acid to isolating water layer, make acidity, use ethyl acetate extraction.The washing organic layer after the drying, heats up in a steamer and desolvates, and obtains the oily resistates.Add ether in resistates, acetone-hexane recrystallization is used in crystallization then, obtains compound (VIII-g, 917mg, 65%).
NMR(DMSO-d 6、TMS)：1.04-1.84(m，19H)，2.63-2.75(m，2H)，2.90-3.05(m，2H)，3.67(s，2H)，3.95-4.20(m，2H)，7.09(m，1H)，7.23-7.32(m，2H)，8.06(d，1H，J＝8.1)，8.24(s，1H)，12.08(s，1H)，12.37(br?s，1H)
Powder x-ray diffraction result such as table 17 and shown in Figure 17.
The diffraction angle of main peaks: 2 θ=6.6,9.8,13.2,16.1,20.1,20.9,24.1 degree
[table 17]
??2θ The d value Intensity Relative intensity
??6.558 ??13.4674 ??67.4 ??59.6
??7.285 ??12.12488 ??21.1 ??18.7
??9.765 ??9.05037 ??76.6 ??67.8
??10.226 ??8.64285 ??53.2 ??47.1
??10.548 ??8.37979 ??11.8 ??10.4
??13.197 ??6.70345 ??67.4 ??59.6
??14.067 ??6.29065 ??33.8 ??29.9
??14.915 ??5.93493 ??21.4 ??18.9
??16.05 ??5.51758 ??59.1 ??52.3
??16.888 ??5.24575 ??9.95 ??8.8
??18.351 ??4.83054 ??38.7 ??34.3
??19.031 ??4.6595 ??32.1 ??28.4
??19.37 ??4.57858 ??32.2 ??28.5
??19.708 ??4.50103 ??37.4 ??33.1
??20.09 ??4.41622 ??91.7 ??81.2
??20.855 ??4.25595 ??104 ??92.2
??22.339 ??3.97649 ??30.2 ??26.7
??22.87 ??3.88526 ??24.4 ??21.6
??24.09 ??3.69114 ??113 ??100
??25.31 ??3.51598 ??30.5 ??27
??25.778 ??3.45322 ??12.3 ??10.9
??26.5 ??3.36071 ??9.03 ??8
??27.674 ??3.22072 ??8 ??7.1
??28.341 ??3.14647 ??10 ??8.8
??28.75 ??3.10262 ??12.9 ??11.4
??29.803 ??2.99537 ??10.3 ??9.1
??30.402 ??2.93767 ??13.3 ??11.8
??30.97 ??2.88513 ??11.9 ??10.5
??32.176 ??2.77966 ??8.35 ??7.4
??32.92 ??2.71848 ??7.08 ??6.3
??34.161 ??2.62251 ??14.1 ??12.5
??34.764 ??2.5784 ??7.62 ??6.7
??35.746 ??2.50978 ??6.53 ??5.8
??36.454 ??2.4627 ??7.46 ??6.6
??37.348 ??2.40576 ??8.57 ??7.6
??38.582 ??2.3316 ??5.86 ??5.2
Synthesizing of embodiment 18 compounds (VIII-h)
[changing 47]
Step 1
Compound (II-j to embodiment 10 acquisitions, 500mg, 1.44mmol), add in the solution of tetrahydrofuran (THF) (5mL) oxalyl chloride (201mg, 1.58mmol) and dimethyl formamide (1), stirred 1 hour down at 25 ℃, obtain to contain the reaction solution of compound (VI-e).This reaction solution is used for the reaction of back.
Step 2
The reaction solution that step 1 is obtained slowly be added drop-wise to compound (VII-d, 320mg, 1.72mmol) and triethylamine (0.435g is in tetrahydrofuran (THF) 4.30mmol) (5mL) solution.Stirred 2 hours down at 25 ℃, obtain to contain the reaction solution of compound (IX-h).Add dilute hydrochloric acid, use ethyl acetate extraction, with saturated sodium bicarbonate water, pure water washing, concentrating under reduced pressure then.Resistates obtains IX-h (600mg, 81%) with acetone-hexane recrystallization.
Step 3
(580mg, 1.12mmol) (3.4mL 3.4mmol), at room temperature stirred 1.5 hours the IX-h that obtains to step 2, added dilute hydrochloric acid, made acidity for middle adding methyl alcohol (3.4mL), tetrahydrofuran (THF) (3.4mL) and 1N aqueous sodium hydroxide solution.Use ethyl acetate extraction, the washing organic layer.To concentrate after the organic layer drying, resistates acetone-hexane recrystallization, the crystal that leaching is separated out, drying obtains compound (VIII-h, 520mg, 95.2%).
NMR(DMSO-d 6、TMS)：1.27-1.49(m，4H)，1.55-1.72(m，4H)，2.67-2.80(m，2H)，2.85-2.97(m，2H)，3.60(s，2H)，5.48(br?s，2H)，6.96-7.04(m，1H)，7.03(s，1H)，7.30-7.46(m，2H)，8.38(s，1H)，12.39(br?s，1H)，13.26(s，1H)
Powder x-ray diffraction result such as table 18 and shown in Figure 180.
The diffraction angle of main peaks: 2 θ=10.0,17.9,18.7,20.6,21.5,21.9 degree
[table 18]
??2θ The d value Intensity Relative intensity
??6.93 ??12.74467 ??14.9 ??17.7
??9.22 ??9.58399 ??4.7 ??5.6
??9.965 ??8.86909 ??48.7 ??57.7
??10.694 ??8.26601 ??8.06 ??9.6
??11.435 ??7.73216 ??10.8 ??12.8
??11.783 ??7.50413 ??6.36 ??7.5
??12.246 ??7.22174 ??14.4 ??17.1
??12.897 ??6.85834 ??23.2 ??27.5
??13.897 ??6.36718 ??14.9 ??17.6
??14.948 ??5.92164 ??35.4 ??42
??16.764 ??5.28428 ??8.47 ??10
??17.855 ??4.96368 ??45.9 ??54.3
??18.48 ??4.79715 ??26.4 ??31.3
??18.728 ??4.7343 ??75.2 ??89.2
??19.652 ??4.51364 ??14.5 ??17.2
??20.595 ??4.30904 ??53.8 ??63.7
??21.536 ??4.12277 ??75.5 ??89.5
??21.871 ??4.06047 ??84.4 ??100
??22.893 ??3.88147 ??18.4 ??21.8
??24.118 ??3.687 ??8.55 ??10.1
??24.732 ??3.59682 ??11.6 ??13.7
??25.731 ??3.45937 ??7.53 ??8.9
??26.261 ??3.39075 ??30.9 ??36.6
??27.083 ??3.28971 ??8.25 ??9.8
??27.799 ??3.20653 ??9.91 ??11.7
??28.488 ??3.13054 ??25.4 ??30
??30.135 ??2.96313 ??11.6 ??13.7
??30.827 ??2.89811 ??12.7 ??15.1
??31.354 ??2.85067 ??9.67 ??11.5
??32.333 ??2.76655 ??5.56 ??6.6
??32.827 ??2.72603 ??11.9 ??14.1
??33.707 ??2.6568 ??5 ??5.9
??36.292 ??2.47327 ??9.49 ??11.2
??36.823 ??2.43882 ??7.03 ??8.3
??37.19??37.769 ??2.41562 ??7.76 ??9.2
??2.37988 ??8.61 ??10.2
??39.238 ??2.29409 ??6.65 ??7.9
??39.846 ??2.26049 ??5.73 ??6.8
Synthesizing of embodiment 19 compounds (VIII-i)
[changing 48]
Figure G2007800518019D00651
Step 1
Compound (II-i to embodiment 9 acquisitions, 300mg, 1.03mmol), add in the solution of tetrahydrofuran (THF) (3mL) oxalyl chloride (143mg, 1.13mmol) and dimethyl formamide (1), stirred 0.5 hour down at 25 ℃, obtain to contain the reaction solution of compound (VI-f).This reaction solution is used for the reaction of back.
Step 2
The reaction solution that step 1 is obtained slowly is added drop-wise to compound, and (VII-g, 260mg is 1.24mmol) and in pyridine (3mL) solution.Stirred 14 hours down at 25 ℃, obtain to contain the reaction solution of compound (IX-i).Add dilute hydrochloric acid, use ethyl acetate extraction, with saturated sodium bicarbonate water, pure water washing, concentrating under reduced pressure then.Resistates by silica gel chromatography (hexane-ethyl acetate (1: 2)) purifying, is obtained IX-i (350mg, 76.1%) with light yellow solid.
Step 3
(340mg, 0.76mmol) (2.3mL 2.3mmol), at room temperature stirred 1 hour the IX-i that obtains to step 2 for middle adding methyl alcohol (2.3mL), tetrahydrofuran (THF) (2.3mL) and 1 Equivalent Hydrogen aqueous solution of sodium oxide.Add dilute hydrochloric acid, make acidity.Use ethyl acetate extraction, the washing organic layer.With organic layer drying, concentrated, with resistates acetone-hexane recrystallization, the crystal that leaching is separated out, drying obtains compound (VIII-I, 250mg, 76.1%).
NMR(DMSO-d 6、TMS)：0.98(d，6H，J＝6.6)，1.26-1.86(m，11H)，2.65-2.80(m，2H)，2.90-3.05(m，2H)，3.81(s，2H)，4.10-4.25(m，2H)，8.32(s，1H)，12.65(br?s，1H)，13.84(s，1H)
Powder x-ray diffraction result such as table 19 and shown in Figure 19.
The diffraction angle of main peaks: 2 θ=10.4,18.0,20.7,21.0 degree
[table 19]
??2θ The d value Intensity Relative intensity
??7.156 ??12.34303 ??7.55 ??1
??10.477 ??8.43668 ??789 ??100
??11.78 ??7.50651 ??6.6 ??0.8
??13.103 ??6.75132 ??24.8 ??3.1
??14.007 ??6.31735 ??16.9 ??2.1
??14.36 ??6.16303 ??8.91 ??1.1
??15.704 ??5.63842 ??17.8 ??2.3
??17.15 ??5.16619 ??29.1 ??3.7
??18.016 ??4.91976 ??63.8 ??8.1
??18.596 ??4.76749 ??28.4 ??3.6
??20.691 ??4.28929 ??60.7 ??7.7
??20.988 ??4.22917 ??52.9 ??6.7
??21.547 ??4.12084 ??17.2 ??2.2
??22.62 ??3.92757 ??13 ??1.7
??23.018 ??3.86056 ??9.8 ??1.2
??23.629 ??3.76217 ??10.8 ??1.4
??24.281 ??3.66264 ??8.27 ??1
??24.867 ??3.5776 ??29.2 ??3.7
??26.363 ??3.37783 ??16.3 ??2.1
??27.151 ??3.28156 ??17.2 ??2.2
??28.762 ??3.10138 ??7.19 ??0.9
??29.739 ??3.00163 ??11.5 ??1.5
??30.329 ??2.94461 ??13.5 ??1.7
??31.724 ??2.81822 ??15.7 ??2
??33.979 ??2.63617 ??10 ??1.3
??38.848 ??2.31625 ??5 ??0.6
Synthesizing of embodiment 20 compounds (VIII-j)
[changing 49]
Figure G2007800518019D00671
Step 1
Compound (II-i to embodiment 4 acquisitions, 300mg, 1.03mmol), add in the solution of tetrahydrofuran (THF) (3mL) oxalyl chloride (143mg, 1.13mmol) and dimethyl formamide (1), stirred 0.5 hour down at 25 ℃, obtain to contain the reaction solution of compound (VI-f).This reaction solution is used for the reaction of back.
Step 2
The reaction solution that step 1 is obtained slowly be added drop-wise to compound (VII-h, 310mg, 1.22mmol) and triethylamine (415mg is 4.1mmol) and in tetrahydrofuran (THF) (3mL) solution.Stirred 14 hours down at 25 ℃, obtain to contain the reaction solution of compound (IX-j).Add dilute hydrochloric acid, use ethyl acetate extraction, with saturated sodium bicarbonate water, pure water washing, concentrating under reduced pressure then.Resistates by silica gel chromatography (hexane-ethyl acetate (2: 1)) purifying, is obtained IX-j (350mg, 76.3%).
Step 3
(340mg, 0.76mmol) (2.3mL 2.3mmol), at room temperature stirred 2.5 hours the IX-j that obtains to step 2 for middle adding methyl alcohol (2.3mL), tetrahydrofuran (THF) (2.3mL) and 1 Equivalent Hydrogen aqueous solution of sodium oxide.Add dilute hydrochloric acid, make acidity.Use ethyl acetate extraction, the washing organic layer.With organic layer drying, concentrated, with resistates acetone-hexane recrystallization, the crystal that leaching is separated out, drying obtains compound (VIII-j, 230mg, 70.1%).
NMR(DMSO-d 6、TMS)：0.98(d，6H，J＝6.6)，1.26-1.84(m，11H)，2.65-2.77(m，2H)，2.90-3.03(m，2H)，3.82(s，2H)，4.10-4.25(m，2H)，7.31(s，1H)，8.24(s，1H)，12.63(br?s，1H)，13.39(s，1H)
Powder x-ray diffraction result such as table 20 and shown in Figure 20.
The diffraction angle of main peaks: 2 θ=9.1,12.1,18.0,18.3,19.7 degree
[table 20]
??2θ The d value Intensity Relative intensity
??8.59 ??10.2848 ??6.48 ??2.1
??9.103 ??9.70638 ??94.3 ??30
??11.69 ??7.56398 ??15.7 ??5
??12.143 ??7.28278 ??314 ??100
??12.676 ??6.9775 ??13.1 ??4.2
??14.963 ??5.91566 ??19.1 ??6.1
??16.459 ??5.38127 ??12.2 ??3.9
??17.536 ??5.05318 ??119 ??38
??18.007 ??4.9222 ??93.9 ??29.9
??18.255 ??4.85589 ??87.4 ??27.8
??18.522 ??4.78638 ??44.1 ??14.1
??18.935 ??4.68288 ??44.2 ??14.1
??19.503 ??4.54787 ??53.1 ??16.9
??19.704 ??4.50176 ??60.6 ??19.3
??19.96 ??4.44466 ??33.2 ??10.6
??20.349 ??4.36048 ??29.4 ??9.4
??20.579 ??4.31244 ??35 ??11.2
??21.386 ??4.15142 ??14.6 ??4.7
??22.764 ??3.90315 ??28.2 ??9
??23.736 ??3.7455 ??18.3 ??5.8
??23.954 ??3.71186 ??23.3 ??7.4
??24.316 ??3.65734 ??13.7 ??4.4
??24.783 ??3.58953 ??13.5 ??4.3
??25.843 ??3.4447 ??8.89 ??2.8
??26.668 ??3.33999 ??47.2 ??15
??27.399 ??3.25242 ??10.2 ??3.2
??28.948 ??3.08184 ??11.7 ??3.7
??29.136 ??3.0624 ??9.3 ??3
??30.006 ??2.97557 ??9.05 ??2.9
??30.971 ??2.88499 ??24.8 ??7.9
??31.478 ??2.83971 ??6.16 ??2
??32.29 ??2.77007 ??9.95 ??3.2
??34.289 ??2.61305 ??15.6 ??5
??34.762 ??2.57857 ??12.3 ??3.9
??35.325 ??2.53873 ??6.28 ??2
??35.734 ??2.5106 ??7.04 ??2.2
??37.371 ??2.40432 ??6.61 ??2.1
??39.096 ??2.30212 ??7.75 ??2.5
Adopt and the same method of embodiment 1-20 synthetic compound (VIII-k)-(VIII-nn).Structural formula is shown in table 21-table 26.
[table 21]
Figure G2007800518019D00691
[table 22]
Figure G2007800518019D00701
[table 23]
Figure G2007800518019D00711
[table 24]
Figure G2007800518019D00721
[table 25]
Figure G2007800518019D00731
Industrial applicability
The inventor found can easy, high yield and high-purity obtain to have the preparation method of the important intermediate of the 2-pyridone of excellent cannabinoid receptor agonists activity-3-carbamoyl derivatives; further find: by using this important intermediate, can high yield and high-purity ground preparation 2-pyridone-3-carbamoyl derivatives.
The accompanying drawing summary
Fig. 1 is compound (II-a) crystalline x-ray diffractogram of powder case and the peak value thereof that embodiment 1 obtains.The longitudinal axis represents that (unit: cps), transverse axis is represented angle of diffraction (2 θ, unit: degree) to intensity.
Fig. 2 is compound (II-b) crystalline x-ray diffractogram of powder case and the peak value thereof that embodiment 2 obtains.The longitudinal axis represents that (unit: cps), transverse axis is represented angle of diffraction (2 θ, unit: degree) to intensity.
Fig. 3 is compound (II-c) crystalline x-ray diffractogram of powder case and the peak value thereof that embodiment 3 obtains.The longitudinal axis represents that (unit: cps), transverse axis is represented angle of diffraction (2 θ, unit: degree) to intensity.
Fig. 4 is compound (II-d) crystalline x-ray diffractogram of powder case and the peak value thereof that embodiment 4 obtains.The longitudinal axis represents that (unit: cps), transverse axis is represented angle of diffraction (2 θ, unit: degree) to intensity.
Fig. 5 is compound (II-e) crystalline x-ray diffractogram of powder case and the peak value thereof that embodiment 5 obtains.The longitudinal axis represents that (unit: cps), transverse axis is represented angle of diffraction (2 θ, unit: degree) to intensity.
Fig. 6 is compound (II-f) crystalline x-ray diffractogram of powder case and the peak value thereof that embodiment 6 obtains.The longitudinal axis represents that (unit: cps), transverse axis is represented angle of diffraction (2 θ, unit: degree) to intensity.
Fig. 7 is compound (II-g) crystalline x-ray diffractogram of powder case and the peak value thereof that embodiment 7 obtains.The longitudinal axis represents that (unit: cps), transverse axis is represented angle of diffraction (2 θ, unit: degree) to intensity.
Fig. 8 is compound (II-h) crystalline x-ray diffractogram of powder case and the peak value thereof that embodiment 8 obtains.The longitudinal axis represents that (unit: cps), transverse axis is represented angle of diffraction (2 θ, unit: degree) to intensity.
Fig. 9 is compound (II-i) crystalline x-ray diffractogram of powder case and the peak value thereof that embodiment 9 obtains.The longitudinal axis represents that (unit: cps), transverse axis is represented angle of diffraction (2 θ, unit: degree) to intensity.
Figure 10 is compound (II-j) crystalline x-ray diffractogram of powder case and the peak value thereof that embodiment 10 obtains.The longitudinal axis represents that (unit: cps), transverse axis is represented angle of diffraction (2 θ, unit: degree) to intensity.
Figure 11 is compound (VIII-a) crystalline x-ray diffractogram of powder case and the peak value thereof that embodiment 11 obtains.The longitudinal axis represents that (unit: cps), transverse axis is represented angle of diffraction (2 θ, unit: degree) to intensity.
Figure 12 is compound (VIII-b) crystalline x-ray diffractogram of powder case and the peak value thereof that embodiment 12 obtains.The longitudinal axis represents that (unit: cps), transverse axis is represented angle of diffraction (2 θ, unit: degree) to intensity.
Figure 13 is compound (VIII-c) crystalline x-ray diffractogram of powder case and the peak value thereof that embodiment 13 obtains.The longitudinal axis represents that (unit: cps), transverse axis is represented angle of diffraction (2 θ, unit: degree) to intensity.
Figure 14 is compound (VIII-d) crystalline x-ray diffractogram of powder case and the peak value thereof that embodiment 14 obtains.The longitudinal axis represents that (unit: cps), transverse axis is represented angle of diffraction (2 θ, unit: degree) to intensity.
Figure 15 is compound (VIII-e) crystalline x-ray diffractogram of powder case and the peak value thereof that embodiment 15 obtains.The longitudinal axis represents that (unit: cps), transverse axis is represented angle of diffraction (2 θ, unit: degree) to intensity.
Figure 16 is compound (VIII-f) crystalline x-ray diffractogram of powder case and the peak value thereof that embodiment 16 obtains.The longitudinal axis represents that (unit: cps), transverse axis is represented angle of diffraction (2 θ, unit: degree) to intensity.
Figure 17 is compound (VIII-g) crystalline x-ray diffractogram of powder case and the peak value thereof that embodiment 17 obtains.The longitudinal axis represents that (unit: cps), transverse axis is represented angle of diffraction (2 θ, unit: degree) to intensity.
Figure 18 is compound (VIII-h) crystalline x-ray diffractogram of powder case and the peak value thereof that embodiment 18 obtains.The longitudinal axis represents that (unit: cps), transverse axis is represented angle of diffraction (2 θ, unit: degree) to intensity.
Figure 19 is compound (VIII-i) crystalline x-ray diffractogram of powder case and the peak value thereof that embodiment 19 obtains.The longitudinal axis represents that (unit: cps), transverse axis is represented angle of diffraction (2 θ, unit: degree) to intensity.
Figure 20 is compound (VIII-j) crystalline x-ray diffractogram of powder case and the peak value thereof that embodiment 20 obtains.The longitudinal axis represents that (unit: cps), transverse axis is represented angle of diffraction (2 θ, unit: degree) to intensity.

Claims (11)

1. the preparation method of the compound shown in the general formula (II), the method includes the steps of:
Steps A with the compound hydrolysis shown in the general formula (I):
Figure A2007800518010002C1
(in the formula, R 1Be the alkyl that can be replaced by non-reacted substituting group, the alkenyl that can be replaced by non-reacted substituting group or the alkynyl that can be replaced by non-reacted substituting group;
R 2And R 3Independent separately, be alkyl, alkoxyalkyl or alkoxyl group; Perhaps
R 2And R 3Can form cyclenes with adjacent carbon atom;
R 4Be hydrogen atom or hydroxyl; And
R 5Be alkyl); With
Add alcohol in the hydrolyzate of the compound shown in the general formula that in steps A, generates (I), obtain the step B of the compound shown in the general formula (II):
Figure A2007800518010002C2
(in the formula, R 1, R 2, R 3And R 4Identical with above-mentioned implication).
2. the described preparation method of claim 1 is characterized in that, carries out steps A and step B continuously.
3. claim 1 or 2 described preparation methods, the method includes the steps of:
The step C of the compound reaction shown in compound shown in the general formula (III) and the general formula (IV):
R 1-NH 2????(III)
(in the formula, R 1Identical with claim 1 implication);
(in the formula, R 2And R 3Identical with claim 1 implication);
And, generate the step D of the compound shown in the general formula (I) with the compound that generates among the step C and the reaction shown in the logical formula V:
Figure A2007800518010003C2
(in the formula, R 4And R 5Identical with claim 1 implication, R 6The expression alkyl);
Figure A2007800518010003C3
(in the formula, R 1, R 2, R 3, R 4And R 5Identical with claim 1 implication).
4. the preparation method of the compound shown in the general formula (VIII):
Figure A2007800518010003C4
(in the formula, R 1, R 2, R 3And R 4It is identical with claim 1 implication,
R 7Be hydrogen atom or alkyl,
X is for can get involved heteroatoms, the alkylidene group that can be replaced by non-reacted substituting group, can get involved heteroatoms, the alkenylene that can be replaced by non-reacted substituting group, can get involved heteroatoms, the alkynylene that can be replaced by non-reacted substituting group, cycloalkanes two bases that can be replaced by non-reacted substituting group, cyclenes two bases that can be replaced by non-reacted substituting group, aromatic hydrocarbons two bases that can be replaced by non-reacted substituting group, assorted aromatic hydrocarbons two bases that can be replaced by non-reacted substituting group, or non-aromatic heterocyclic two bases that can be replaced by non-reacted substituting group
Y is singly-bound, the alkylidene group that can be replaced by non-reacted substituting group, the alkenylene that can be replaced by non-reacted substituting group or the alkynylene that can be replaced by non-reacted substituting group),
The method includes the steps of:
The step C of the compound reaction shown in compound shown in the general formula (III) and the general formula (IV):
R 1-NH 2????(III)
(in the formula, R 1Identical with claim 1 implication);
Figure A2007800518010004C1
(in the formula, R 2And R 3Identical with claim 1 implication);
With compound and the reaction of the compound shown in the logical formula V that generates among the step C, generate the step D of the compound shown in the general formula (I):
(in the formula, R 4And R 5Identical with claim 1 implication, R 6Identical with claim 3 implication);
Figure A2007800518010004C3
(in the formula, R 1, R 2, R 3, R 4And R 5Identical with claim 1 implication);
The steps A that compound shown in the general formula (I) is hydrolyzed;
In the hydrolyzate of the compound shown in the general formula that in steps A, generates (I), add alcohol, obtain the step B of the compound shown in the general formula (II):
(in the formula, R 1, R 2, R 3And R 4Identical with claim 1 implication);
With compound shown in the general formula (II) and halide reagent reaction, generate the step e of the compound shown in the general formula (VI):
Figure A2007800518010005C2
(in the formula, R 1, R 2, R 3And R 4Identical with claim 1 implication, Hal is a halogen atom);
And with the reaction of the compound shown in compound shown in the general formula (VI) and the general formula (VII), the step F of the reaction that is hydrolyzed as required:
Figure A2007800518010005C3
(in the formula, R 7, X, Y be identical with above-mentioned implication).
5. claim 3 or 4 described preparation methods is characterized in that, carry out step C, D, A and B continuously.
6. each described preparation method among the claim 1-5 wherein, obtains the compound shown in the general formula (II) with the crystalline form.
7. each described preparation method among the claim 1-6, wherein, R 1Be the alkyl that can be replaced by non-reacted substituting group, R 2Be C1-C2 alkyl, R 3Be C1-C3 alkyl, R 4Be hydrogen atom, R 5Be the C1-C2 alkyl.
8. each described preparation method among the claim 1-6, wherein, R 1Be the alkyl that can be replaced by non-reacted substituting group, R 2And R 3Form cyclooctene with adjacent carbon atom, R 4Be hydrogen atom, R 5Be the C1-C2 alkyl.
9. claim 7 or 8 described preparation methods, wherein, the alcohol that is added is Virahol.
10. the crystalline preparation method of the compound shown in the general formula (II) is characterized in that, adds alcohol in the solution that contains the compound shown in the general formula (II):
(in the formula, R 1, R 2, R 3And R 4Identical with claim 1 implication).
11. the described preparation method of claim 10, wherein, alcohol is Virahol.
CN200780051801A 2006-12-27 2007-12-25 Process for producing 1-substituted-2-pyridone-3-carboxylic acid derivative Pending CN101668744A (en)

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