CN101490009A - Synthesis of acylaminoalkenylene amides useful as substance P antagonists. - Google Patents
Synthesis of acylaminoalkenylene amides useful as substance P antagonists. Download PDFInfo
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- CN101490009A CN101490009A CNA2007800126883A CN200780012688A CN101490009A CN 101490009 A CN101490009 A CN 101490009A CN A2007800126883 A CNA2007800126883 A CN A2007800126883A CN 200780012688 A CN200780012688 A CN 200780012688A CN 101490009 A CN101490009 A CN 101490009A
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Abstract
The invention relates to a process for preparing compounds of formula (I) or a solvate or hydrate thereof, where R, R<1>, R<2>, R<3> and R<5> have the meanings as indicated in the specification. Such compounds are useful in the treatment of a number of conditions associated with substance P and neurokinin.
Description
The present invention relates to organic compound, the particularly preparation of acyl amino eneamide derivatives P substance antagonist.
More specifically, the present invention relates to the method for preparation I compound or its solvate or hydrate
Wherein
R is unsubstituted or by 1,2 or 3 phenyl that substituting group replaced, described substituting group is selected from halogen, C
1-C
7-alkyl, trifluoromethyl, hydroxyl and C
1-C
7-alkoxyl group;
R
1Be hydrogen or C
1-C
7-alkyl;
R
2Be hydrogen, C
1-C
7-alkyl or unsubstituted or by 1,2 or 3 phenyl that substituting group replaced, described substituting group is selected from halogen, C
1-C
7-alkyl, trifluoromethyl, hydroxyl and C
1-C
7-alkoxyl group;
R
3For unsubstituted or by 1,2 or 3 phenyl that substituting group replaced, described substituting group is selected from halogen, C
1-C
7-alkyl, trifluoromethyl, hydroxyl and C
1-C
7-alkoxyl group, perhaps R
3Be naphthyl, 1H-indol-3-yl or 1-C
1-C
7-alkyl-indol-3-yl; And
R
5Be C
3-C
8-cycloalkyl, D-azepan-2-ketone-3-base or L-azepan-2-ketone-3-base.
The compound of formula I is effective in the many illnesss relevant with neurokinin with the P material of treatment.
Particularly preferred formula I compound is N-[(E)-(R)-1-(3,4-two chloro-benzyls)-3-((R)-2-oxo-azepan-3-base formamyl)-allyl group]-N-methyl-3,5-di-trifluoromethyl-benzamide.It also is called as N-[(R; R)-(E)-1-(3; the 4-dichloro benzyl)-3-(2-oxo azepan-3-yl)-formamyl]-allyl group-N-methyl-3; 5-two (trifluoromethyl)-benzamide and (4R)-4-[N '-methyl-N '-(3; 5-bis trifluoromethyl-benzoyl)-amino]-4-(3; the 4-dichloro benzyl)-but-2-ene acid N-[(R)-ε-Ji Neixianan-3-yl]-acid amides, and it has the chemical structure of formula A
The compound of formula A, especially its semihydrate are used for the treatment of viscera function sexuality disorder, and for example irritable bowel syndrome or functional dyspepsia, especially diarrhoea are main irritable bowel syndrome.
The compound of formula I can use the method preparation of describing in the International Patent Application WO 98/07694, and its content is incorporated herein by reference.
And the present invention relates to improving one's methods of preparation I compound and solvate and hydrate; especially (4R)-4-[N '-methyl-N '-(3; 5-bis trifluoromethyl-benzoyl)-amino]-4-(3; the 4-dichloro benzyl)-but-2-ene acid N-[(R)-ε-Ji Neixianan-3-yl]-acid amides; it has the security and the wholesomeness of height, and operation easily.It also helps to obtain productive rate preferably on producing.
First aspect the invention provides the method for preparation I compound or its solvate or hydrate
Wherein
R is unsubstituted or by 1,2 or 3 phenyl that substituting group replaced, described substituting group is selected from halogen, C
1-C
7-alkyl, trifluoromethyl, hydroxyl and C
1-C
7-alkoxyl group;
R
1Be hydrogen or C
1-C
7-alkyl;
R
2Be hydrogen, C
1-C
7-alkyl or unsubstituted or by 1,2 or 3 phenyl that substituting group replaced, described substituting group is selected from halogen, C
1-C
7-alkyl, trifluoromethyl, hydroxyl and C
1-C
7-alkoxyl group;
R
3For unsubstituted or by 1,2 or 3 phenyl that substituting group replaced, described substituting group is selected from halogen, C
1-C
7-alkyl, trifluoromethyl, hydroxyl and C
1-C
7-alkoxyl group, perhaps R
3Be naphthyl, 1H-indol-3-yl or 1-C
1-C
7-alkyl-indol-3-yl; And
R
5Be C
3-C
8-cycloalkyl, D-azepan-2-ketone-3-base or L-azepan-2-ketone-3-base,
Described method comprises the steps:
(a) with the compound of formula II, R wherein
1, R
2, R
3And R
5As hereinbefore defined, T is a protecting group,
With the compound of alkali reaction formation formula III,
R wherein
1, R
2, R
3And R
5As hereinbefore defined; With
(b) incite somebody to action wherein R
1, R
2, R
3And R
5The compound of formula III as hereinbefore defined and formula IV compound,
Wherein R is unsubstituted or is selected from halogen, C by 1,2 or 3
1-C
7-alkyl, trifluoromethyl, hydroxyl and C
1-C
7The phenyl that substituting group replaced of-alkoxyl group, and X is halogen, reaction forms the compound of formula I in the presence of alkali; And
(c) randomly form required its solvate or hydrate.
Second aspect the invention provides the method for preparation I compound or its solvate or hydrate
Wherein
R is unsubstituted or by 1,2 or 3 phenyl that substituting group replaced, described substituting group is selected from halogen, C
1-C
7-alkyl, trifluoromethyl, hydroxyl and C
1-C
7-alkoxyl group;
R
1Be hydrogen or C
1-C
7-alkyl;
R
2Be hydrogen, C
1-C
7-alkyl or unsubstituted or by 1,2 or 3 phenyl that substituting group replaced, described substituting group is selected from halogen, C
1-C
7-alkyl, trifluoromethyl, hydroxyl and C
1-C
7-alkoxyl group;
R
3For unsubstituted or by 1,2 or 3 phenyl that substituting group replaced, described substituting group is selected from halogen, C
1-C
7-alkyl, trifluoromethyl, hydroxyl and C
1-C
7-alkoxyl group; Perhaps R
3Be naphthyl, 1H-indol-3-yl or 1-C
1-C
7-alkyl-indol-3-yl; And
R
5Be C
3-C
8-cycloalkyl, D-azepan-2-ketone-3-base or L-azepan-2-ketone-3-base;
Described method comprises the steps:
(i) with the compound of formula V,
R wherein
1, R
2And R
3As hereinbefore defined, and T is protecting group,
In the presence of alkali with 2,2-dimethyl-[1,3] diox-4,6-two reactive ketones form the compound of formula VI
R wherein
1, R
2And R
3As hereinbefore defined, and T be protecting group;
(ii) incite somebody to action wherein R
1, R
2And R
3As hereinbefore defined and T be the compound of formula VI and the methyl alcohol reaction of protecting group, obtain the compound of formula VII,
R wherein
1, R
2And R
3As hereinbefore defined, and T be protecting group;
(iii) incite somebody to action wherein R
1, R
2And R
3As hereinbefore defined and T be the compound reduction of the formula VII of protecting group, form the compound of formula VIII
R wherein
1, R
2And R
3As hereinbefore defined, and T be protecting group;
(iv) incite somebody to action wherein R
1, R
2And R
3As hereinbefore defined and T be the compound hydrolysis of the formula VIII of protecting group, obtain the carboxylic acid of corresponding formula IX
R wherein
1, R
2And R
3As hereinbefore defined, and T be protecting group;
(v) incite somebody to action wherein R
1, R
2And R
3As hereinbefore defined and T be the compound of formula IX and the reaction of formula X compound of protecting group
H
2N—R
5 X
R wherein
5Be C
3-C
8-cycloalkyl, D-azepan-2-ketone-3-base or L-azepan-2-ketone-3-base,
Form the compound of formula II
R wherein
1, R
2And R
3As hereinbefore defined, and T is protecting group, and R
5Be C
3-C
8-cycloalkyl, D-azepan-2-ketone-3-base or L-azepan-2-ketone-3-base;
(vi) purifying R wherein randomly
1, R
2, R
3And R
5As hereinbefore defined and T be the formula II compound of protecting group;
(vii) incite somebody to action wherein R
1, R
2, R
3And R
5As hereinbefore defined and T be the formula II compound and the alkali reaction of protecting group, form the compound of formula III
R wherein
1, R
2, R
3And R
5As hereinbefore defined;
(viii) incite somebody to action wherein R
1, R
2, R
3And R
5Formula III compound as hereinbefore defined and the compound of formula IV,
Wherein R is unsubstituted or is selected from halogen, C by 1,2 or 3
1-C
7-alkyl, trifluoromethyl, hydroxyl and C
1-C
7The phenyl that substituting group replaced of-alkoxyl group, and X is halogen,
Reaction forms the compound of formula I, wherein R, R in the presence of alkali
1, R
2, R
3And R
5As hereinbefore defined; With
(ix) randomly form required its solvate or hydrate.
Used term has following implication in specification sheets:
" halogen " used herein expression belongs to periodic table of elements family 17 element of (being called VII family in the past), and it can be for example fluorine, chlorine, bromine or iodine.Preferred halogen is chlorine or bromine, especially chlorine.
" C used herein
1-C
7-alkyl " expression comprises the alkyl of straight or branched of 1-7 carbon atom, and it can be the amyl group of for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, straight or branched, the hexyl of straight or branched or the heptyl of straight or branched.
" C used herein
1-C
7-alkoxyl group " alkyl of the straight or branched that links to each other with oxygen of expression, it can be the pentyloxy of for example methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy, straight or branched, the hexyloxy of straight or branched or the oxygen base in heptan of straight or branched.
" C used herein
3-C
8-cycloalkyl " expression has the complete saturated carbocyclic ring of 3-8 ring carbon atom, for example monocyclic groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl or encircle octyl group, or bicyclic groups encircles octyl groups as two suberyl or two.
Unless context has needs in addition, in whole specification sheets and appending claims, term " comprise " or its variant as " comprising ", should be understood to comprise the group of described integral body or step or integral body or step, but do not get rid of the group of any other integral body or step or integral body or step.
According to formula I, following the present invention suitable, preferred, preferred or most preferred aspect can be separately, common or merge with the form of any combination.
What R was suitable is that described substituting group is selected from halogen, C by 1,2 or 3 phenyl that substituting group replaced
1-C
7-alkyl, trifluoromethyl, hydroxyl and C
1-C
7-alkoxyl group.
When R is by C
1-C
7During phenyl that-alkyl replaces, what it was suitable is by C
1-C
4The phenyl that-alkyl replaces.And work as R is by C
1-C
7During phenyl that-alkoxyl group replaces, what it was suitable is by C
1-C
4The phenyl that-alkoxyl group replaces.
R is the phenyl for being replaced by trifluoromethyl on one or two position, particularly two positions more suitably.R particularly 3,5-di-trifluoromethyl-phenyl.
R
1That suitable is C
1-C
7-alkyl more suitably is C
1-C
4-alkyl, but specially suitable be methyl.
R
1That suitable is hydrogen or C
1-C
7-alkyl.
R
2Suitable is hydrogen.
R
3Suitable is that described substituting group is selected from halogen, C by 1,2 or 3 phenyl that substituting group replaced
1-C
7-alkyl, trifluoromethyl, hydroxyl and C
1-C
7-alkoxyl group.
R
3More suitably on one or two position, particularly two positions by halogen, phenyl that particularly chlorine replaced.R
3Specially suitable is 3,4-two chloro-phenyl.
R
5Suitable is D-azepan-2-ketone-3-base.
Formula I compound or the midbody compound that is used for preparation I compound can be respectively pharmaceutically acceptable isotope-labeled formula I compound or the midbody compound that is used for preparation I compound, and wherein one or more atoms are had the same atoms ordinal number but common atomic mass or the different atom of total mass number that atomic mass or total mass number and occurring in nature are found are replaced.The suitable isotopic example that is comprised in the The compounds of this invention comprises: the isotropic substance of hydrogen, for example
2H and
3H; Carbon isotope, for example
11C,
13C and
14C; Chlorine isotope, for example
36Cl; Fluorine isotope, for example
18F; Iodine isotope, for example
123I and
125I; Nitrogen isotope, for example
13N and
15N; Oxygen isotope, for example
15O,
17O and
18O; And sulfur isotope, for example
35S.
Some isotope-labeled formula I compound, for example those mix radioisotopic compound, are useful in the tissue distribution research of medicine and/or substrate.The radio isotope tritium (
3H) and carbon-14 (
14C) because it is easy to mix and the detection method convenience, be useful especially in this respect.Heavy isotope for example deuterium (
2H) replacement can provide some treatment advantage that causes owing to higher metabolic stability, and for example the transformation period increases or the required dosage reduction in the body, can be preferred in some cases therefore.The positron radiation isotropic substance for example
11C,
18F,
15O and
13The displacement of N is used to check the occupancy of substrate acceptor in PET (positron emission tomography) (PET) research.
Isotope-labeled formula I compound or the isotope-labeled intermediate compound that is used for preparation I compound can obtain by routine techniques known in those skilled in the art usually, perhaps by with the similar method of method described in the appended embodiment, use suitable isotope-labeled reagent to replace the previous unmarked reagent that uses and obtain.
Pharmaceutically acceptable solvate of the present invention comprises the solvate that those recrystallisation solvents can be replaced by isotropic substance, and described solvent is D for example
2O, d
6-acetone or d
6-DMSO.
The compound of formula I can adopt following multistep method, from formula V compound,
R wherein
1, R
2And R
3Define as mentioned, and T is a protecting group.
In step 1 and 2, with 2 carbon atoms of formula V compound prolongation of above-mentioned definition.
In step 1, incite somebody to action wherein R
1, R
2And R
3Define as mentioned and T be the compound of formula V of protecting group and 2.2-dimethyl-[1,3] diox-4,6-diketone (Michaelis acid (meldrum ' s acid)) in the presence of alkali, react, form the compound of formula VI
R wherein
1, R
2And R
3Define in as mentioned, and T is protecting group or for example is similar to described in hereinafter the embodiment.
This step is adapted at alkali and for example carries out under dimethyl-pyridin-4-yl-amine existence.It for example carries out in the toluene easily at organic solvent.Temperature of reaction can be for example from room temperature to 60 ℃, preferred 25 ℃-35 ℃.
Protecting group T can be selected from the protecting group that is suitable for this functional group's character, for example referring to ProtectiveGroups in Organic Synthesis, T.W.Greene and P.G.M.Wuts, John Wiley ﹠amp; Sons Inc, second edition, 1991, this reference has also been described the proper method of replacing protecting group with hydrogen.That described protecting group is suitable is tert-butoxycarbonyl or BOC.
In WO 98/07694, in the method for disclosed preparation I compound, obtain drug substance by two diastereomeric separation with the later stage intermediate.This method has caused losing raw material over half.Method of the present invention originates in the compound of optically active, has avoided this problem, therefore significantly improves productive rate and has reduced waste.
In step 2, incite somebody to action wherein R
1, R
2And R
3Define as mentioned and T is that compound and the methyl alcohol of the formula VI of protecting group reacts, preferably under the condition of water existence, carry out the compound of acquisition formula VII
R wherein
1, R
2And R
3As hereinbefore defined, and T be protecting group or for example be similar to described in hereinafter the embodiment.
In step 3, incite somebody to action wherein R
1, R
2And R
3Define as mentioned and T is the compound reduction of the formula VII of protecting group, acquisition is (R)-oxy-compound, the i.e. compound of formula VIII accordingly
R wherein
1, R
2And R
3Define as mentioned, and T is a protecting group.The method of known reductone is adopted in this reaction or the method described in the embodiment that for example is similar to is hereinafter carried out.Be reflected in the mixture of organic solvent (for example tertiary butyl methyl ester and methyl alcohol) and water and carry out easily, what reductive agent was suitable is sodium borohydride.This reaction can at room temperature be carried out, but suitable temperature is 15 ℃-25 ℃.
(the R)-oxy-compound of gained has the correct configuration of formation trans double bond subsequently.
In step 4, incite somebody to action wherein R
1, R
2And R
3Define and T is the compound hydrolysis of the formula VIII of protecting group acquisition corresponding carboxylic acid, the i.e. compound of formula IX as mentioned.
R wherein
1, R
2And R
3Define as mentioned, and T is a protecting group.This reaction adopts known hydrolysis lipid to form the method for carboxylic acid or the method described in the embodiment that for example is similar to is hereinafter carried out.Be reflected in the mixture of water-miscible organic solvent (for example tertiary butyl methyl ester and methyl alcohol) and water and carry out easily.What hydrolysing agent was suitable is highly basic, for example lithium hydroxide monohydrate.This reaction can at room temperature be carried out, but preferred 15 ℃-25 ℃.
In step 5, incite somebody to action wherein R
1, R
2And R
3Define as mentioned and T is that the compound of formula IX of protecting group and the compound of formula X react
H
2N—R
5 X
R wherein
5Be C
3-C
8-cycloalkyl, D-azepan-2-ketone-3-base or L-azepan-2-ketone-3-base,
Form the compound of formula II
R wherein
1, R
2And R
3Define in as mentioned, and T is protecting group, and R
5Be C
3-C
8-cycloalkyl, D-azepan-2-ketone-3-base or L-azepan-2-ketone-3-base.
Reaction adopts the known method or the method described in the embodiment that for example is similar to hereinafter with carboxylic acid and amine reaction formation amide derivatives to carry out.Be reflected in organic solvent such as the N-N-dimethyl-methane amide and carry out easily.This reaction is fit at room temperature carry out, but preferred 15 ℃-25 ℃.
In step 6, the compound of purifying formula II is promptly removed unwanted isomer.Surprisingly, just this step by in organic solvent such as t-butyl methyl ether, can obtain high-purity product simply in room temperature to 60 ℃ following stirring, suitable temperature is 45 ℃-55 ℃, but specially suitable be about 50 ℃.
In step 7, incite somebody to action wherein R
1, R
2, R
3And R
5As hereinbefore defined and T be the compound of formula II of protecting group and the compound that alkali reaction forms formula III
R wherein
1, R
2, R
3And R
5Define as mentioned.Under the normal circumstances, in beta-hydroxy esters or acid amides, hydroxyl at first must change into leavings group, eliminates reaction subsequently under alkali is induced, and forms trans double bond.Yet surprisingly, introducing trans double bond in step 7 is one to go on foot the method for removing (R) hydroxyl and BOC group simultaneously by the alkali inductive.And this reaction does not take place in the isomeric compound that has (S) configuration hydroxyl accordingly.
This is reflected in organic solvent such as the tetrahydrofuran (THF) and carries out easily.
Temperature of reaction can be for example-10 ℃-10 ℃, and suitable temperature is-5 ℃-5 ℃, but specially suitable temperature is-2 ℃-2 ℃.The reaction conditions that provides is optimized so that the formation of by product reduces: when for example using the stronger alkali of ethanolic soln than sodium ethylate, observe the epimerization that more cis-double bonds forms, the conversion of two key forms enamine and hexanolactam part.Then need the longer reaction times when using weak base, and only finished the conversion of part.
In step 8, incite somebody to action wherein R
1, R
2, R
3And R
5The compound of defined formula III compound and formula IV reacts in the presence of alkali as mentioned
Wherein R is unsubstituted or is selected from halogen, C by 1,2 or 3
1-C
7-alkyl, trifluoromethyl, hydroxyl and C
1-C
7The phenyl that substituting group replaced of-alkoxyl group, and X is halogen, suitable is chlorine,
Form formula I compound or its salt, wherein R, R
1, R
2, R
3And R
5Define as mentioned.
Reaction adopts the known method or the method described in the embodiment that for example is similar to hereinafter with amine and carboxylic acid halides prepared in reaction amide derivatives to carry out.Be reflected in organic solvent such as the t-butyl methyl ether and carry out easily, described alkali is for example triethylamine.Temperature of reaction can be for example-10 ℃-20 ℃, and suitable temperature is-5 ℃-15 ℃, but specially suitable be 0 ℃-5 ℃.
In this optional step of step 9, incite somebody to action wherein R, R
1, R
2, R
3And R
5As mentioned defined formula I compound in suitable solvent crystallization to obtain free cpds, solvate or hydrate.
The formula I compound of gained can be free cpds, its hydrate or contain the solvate forms that is useful on the crystalline solvent.For example, when formula I compound is the compound of formula A, with its from the first alcohol and water crystallization to obtain stable medicine semihydrate.
Illustrate the present invention by following examples.
Embodiment
N-[(E)-(R)-1-(3,4-two chloro-benzyls)-3-((R)-2-oxo-azepan-3-base formamyl)-allyl group]-N-methyl-3, the preparation of 5-di-trifluoromethyl-benzamide semihydrate
N-[(E)-(R)-1-(3,4-two chloro-benzyls)-3-((R)-2-oxo-azepan-3-base formamyl)-allyl group]-N-methyl-3,5-di-trifluoromethyl-benzamide semihydrate prepares by the following method.All being reflected under the nitrogen atmosphere carried out.
Step 1+2:(R)-4-(tert-butoxycarbonyl-methyl-amino)-5-(3,4-two chloro-phenyl)-3-oxo
-methyl valerate (4)
Under 29-31 ℃, go through about 1 hour with 1,3-dicyclohexylcarbodiimide (2.9011g, 13.9mmol) toluene solution (3ml) join (R)-2-(tert-butoxycarbonyl-methyl-amino)-3-(3 under stirring, 4-two chloro-phenyl)-and propionic acid (1,4.179g, 12mmol), 2,2-dimethyl-[1,3] dioxs-4, and the 6-diketone (2,1.7815g, 12.36mmol) and dimethyl-pyridin-4-yl-amine (2.0943g is 16.8mmol) in the mixture of toluene (32ml).With toluene (1ml) drip washing.Continuation was stirred about 3 hours down at 29-31 ℃.After being cooled to about 0 ℃, adding the potassium hydrogen sulfate solution (about 9ml) of 25%w/w under-2 ℃/2 ℃ in suspension, is 2-3 up to pH.Stop to stir, make it layering.Mixture is slowly stirred cold filtration (0-5 ℃), filter cake toluene (12ml, 0-5 ℃) drip washing.Each layer of filtrate is in about 0-5 ℃ lower leaf.The water layer that separates lower floor.The organic layer on upper strata contain intermediate [(R)-1-(3,4-two chloro-benzyls)-2-(2,2-dimethyl-4,6-dioxo-[1,3] diox-5-yl)-2-oxo-ethyl]-methyl-carboxylamine tertiary butyl ester (3), under 0-5 ℃ with it by the strainer of anhydrous sodium sulphate (5g) is housed, and filtrate joining contained in the reactor of methyl alcohol (18ml, 20-25 ℃).Filter cake toluene (5ml) drip washing, filtrate joins in the reactor equally.Heating gained solution (about 68 ℃ of outer sheath temperature), about 63 ℃ of following stir abouts 4 hours, be about 50 ℃ of following concentrating under reduced pressure in outer sheath temperature subsequently, obtain the oily resistates, it is dissolved under about 50 ℃ outer sheath temperature and normal pressure in the t-butyl methyl ether (24ml), concentrating under reduced pressure once more obtains oily resistates (R)-4-(tert-butoxycarbonyl-methyl-amino)-5-(3,4-two chloro-phenyl)-3-oxo-methyl valerate (4) subsequently.This resistates is dissolved in the t-butyl methyl ether (24ml) under 50 ℃ outer sheath temperature and normal pressure once more, is cooled to 18-22 ℃ subsequently, be directly used in next step.
Step 3:(3R, 4R)-4-(tert-butoxycarbonyl-methyl-amino)-5-(3,4-two chloro-phenyl)-3-hydroxyl
-methyl valerate (5)
(R)-4-(tert-butoxycarbonyl-methyl-amino)-5-(3,4-two chloro-the phenyl)-3-oxo-methyl valerate (4) under stirring under 18-22 ℃ in the solution of t-butyl methyl ether, add sodium borohydride (0.227g, 6mmol).Went through about 20 minutes, and under 18-22 ℃, added entry (3ml), continue stir about 15 minutes subsequently.Went through about 30 minutes, and added methyl alcohol (3ml) down, continue stir about 30 minutes subsequently at 18-22 ℃, obtain (3R, 4R)-and 4-(tert-butoxycarbonyl-methyl-amino)-5-(3,4-two chloro-phenyl)-3-hydroxyl-methyl valerate (5) solution, be directly used in next step.
Step 4:(3R, 4R)-4-(tert-butoxycarbonyl-methyl-amino)-5-(3,4-two chloro-phenyl)-3-hydroxyl
-valeric acid (6)
Under stirring, containing (3R under 18-22 ℃, 4R)-4-(tert-butoxycarbonyl-methyl-amino)-5-(3,4-two chloro-phenyl)-add entry (3ml) in the reaction mixture of 3-hydroxyl-methyl valerate (5), add subsequently a hydronium(ion) oxidation lithium (0.755g, 18mmol).Lasting stir about is 2 hours under 18-22 ℃.Go through about 30 minutes adding hydrochloric acid (the 2N hydrochloric acid of about 12.6ml, 25.2mmol)), reach 1.7-2.2 up to pH.Add toluene (12ml) in stirred mixture, lasting stir about is 10 minutes under 18-22 ℃.Stop to stir, make it layering.Separate lower aqueous layer, upper strata organic layer water extraction (12ml).Stop to stir, separate lower aqueous layer.Organic layer filters with the filter that anhydrous sodium sulphate (3g) is housed, removing residual water and 1, and the 3-dicyclohexylurea (DCU), the latter is from step 1.Filter cake adds N, dinethylformamide (12ml) subsequently with toluene drip washing (2ml) in filtrate.Gained solution is about 50 ℃ down by the toluene distillation concentrating under reduced pressure in outer sheath temperature, is about 14ml until the resistates volume.The containing of gained (3R, 4R)-solution of 4-(tert-butoxycarbonyl-methyl-amino)-5-(3,4-two chloro-phenyl)-3-hydroxyl-valeric acid (6) is directly used in subsequent step.
Step 5:[(1R, 2R)-1-(3,4-two chloro-benzyls)-2-hydroxyl-3-((R)-2-oxo-azepan
-3-base formamyl)-propyl group]-methyl-t-butyl carbamate (8)
(1.396g=1.91ml, 13.8mmol) (the R)-3-amino-azepan-2-keto hydrochloride (7) that joins stirring in the mixture of dinethylformamide (12ml), continues stir about 1 hour at N subsequently with triethylamine under 18-22 ℃.Under 18-22 ℃, in stirred mixture, add I-hydroxybenzotriazole hydrate (2.113g, 13.8mmol), add subsequently (3R, 4R)-4-tert-butoxycarbonyl-methyl-amino)-5-(3,4-two chloro-phenyl)-and the N of 3-hydroxyl-valeric acid (6), dinethylformamide solution.Use N, dinethylformamide (2ml) carries out drip washing.Mixture is cooled to 0-5 ℃, adds 1 subsequently, and (2.847g 13.8mmol), uses N to the 3-dicyclohexylcarbodiimide then, dinethylformamide (1.5ml) drip washing.Lasting stir about is 1 hour under about 0-5 ℃, and with extremely about 18-22 ℃ of mixture heating up, stir about is 20 hours under this temperature subsequently.Remove by filter precipitated solid, filter cake N, dinethylformamide (12ml) drip washing.Filtrate is at the about 60 ℃ of following concentrating under reduced pressure of outer sheath temperature, up to the enriched material that obtains about 19.5g.The gained suspension is cooled to about 20-25 ℃, went through subsequently about 20 minutes, generate at the same time and add saleratus under the situation of carbonic acid gas (1.92g, aqueous solution 19.17mmol) (32ml) obtains suspension.Remove by filter precipitated solid; with water wash (24ml); in about 60 ℃ of following vacuum-dryings to constant weight; obtain thick [(1R; 2R)-1-(3,4-two chloro-benzyls)-2-hydroxyl-3-((R)-2-oxo-azepan-3-base formamyl)-propyl group]-(6.019g is according to (R)-2-(tert-butoxycarbonyl-methyl-amino)-3-(3 for methyl-t-butyl carbamate (8); 4-two chloro-phenyl-propionic acid (1), theoretical yield is 99.8%).
Step 6:[(1R, 2R)-1-(3,4-two chloro-benzyls)-2-hydroxyl-3-((R)-2-oxo-azepan
-3-base formamyl)-propyl group]-methyl-t-butyl carbamate (9)
Following at about 20-25 ℃ with [(1R; 2R)-1-(3,4-two chloro-benzyls)-2-hydroxyl-3-((R)-2-oxo-azepan-3-base formamyl)-propyl group]-methyl-carboxylamine tertiary butyl ester (8) (6.019g) joins in the t-butyl methyl ether (35ml) of stirring.To about 50-52 ℃, stir about is 1 hour under this temperature with described mixture heating up.Suspension is cooled to about 0-5 ℃, and stir about is 1 hour under this temperature.The filtering separation precipitated solid; with t-butyl methyl ether drip washing (24ml); in about 70 ℃ of following vacuum-dryings to constant weight; obtain [(1R, 2R)-1-(3,4-two chloro-benzyls)-2-hydroxyl-3-((R)-2-oxo-azepan-3-base formamyl)-propyl group]-methyl-t-butyl carbamate (9) (4.2625g; according to (R)-2-(tert-butoxycarbonyl-methyl-amino)-3-(3,4-two chloro-phenyl)-propionic acid (1), theoretical yield is 70.7%.Purity: 98.5% area (hplc).Product is further purified by crystallization from methylene dichloride/t-butyl methyl ether.M.p.186.8-187.4 ℃, MS-ES
+: (MNa)
+=524 (
35Cl
2), [α]
D 20=+17.24 ° (94% ethanol).
Step 7:(E)-(R)-5-(3,4-two chloro-phenyl)-4-methylamino-penta-2-olefin(e) acid ((R)-2-oxo-
Azepan-3-yl)-acid amides (10)
With the [(1R under stirring; 2R)-1-(3; 4-two chloro-benzyls)-2-hydroxyl-3-((R)-2-oxo-azepan-3-base-formamyl)-propyl group]-methyl-carboxylamine tertiary butyl ester (9) (1.005g; 2.0mmol) and the mixture of tetrahydrofuran (THF) (12ml) be cooled to-2 ℃/2 ℃; under-2 ℃/2 ℃, go through subsequently the ethanolic soln that added the 21%w sodium ethylate in about 20 minutes (1.5ml, 4.0mmol).Gained solution is gone through the potassium bicarbonate aqueous solution (0.253g, 2.53mmol is in 4.81g water) that added 5%w in about 10 minutes subsequently about 0 ℃ of following stir about 4.5 hours under about 0 ℃.Temperature is risen to about 20 ℃, add toluene (17ml) subsequently.After stirring the mixture about 16 hours under about 20 ℃, stop to stir, make it layering.Separate lower aqueous layer, organic layer water extraction (3.5ml).Organic layer is at 60 ℃ of following concentrating under reduced pressure of outer sheath temperature, and the resistates up to obtaining about 10g makes the product crystallization.After 10 minutes, continue distillation at 60 ℃ of following stir abouts, up to obtaining about 5g resistates.Add entry (0.36ml), continued stir about 30 minutes down at 60 ℃.Mixture is gone through and was cooled to about 0 ℃ in about 30 minutes, continues stir about 2 hours subsequently under this temperature.The solid by filtration of separating out is separated, filter cake toluene drip washing (3ml).In about 60 ℃ of following vacuum-dryings to constant weight, obtain (E)-(R)-5-(3,4-two chloro-phenyl)-and 4-methylamino-penta-2-olefin(e) acid ((R)-2-oxo-azepan-3-yl)-acid amides (10) (0.580g is 75.5% according to the theoretical yield of (9)): m.p.153-158 ℃, MS-ES
+: (MH)
+=384 (
35Cl
2), [α]
D 20=-80.4 ° (ethanol).
Step 8:N-[(E)-(R)-1-(3,4-two chloro-benzyls)-3-((R)-2-oxo-azepan-3-base ammonia
The base formyl radical)-allyl group]-N-methyl-3,5-di-trifluoromethyl-benzamide (12)
With the E under stirring)-(R)-(3,4-two chloro-phenyl)-(1.1529g, 3mmol) mixture in t-butyl methyl ether (10ml) is cooled to about 0 ℃ 4-methylamino-penta-2-olefin(e) acid ((R)-2-oxo-azepan-3-yl)-acid amides (10) 5-.Under 0-5 ℃, go through and added 3 in about 15 minutes, 5-di-trifluoromethyl-Benzoyl chloride (0.87g=0.57ml, 3.15mmol), subsequently under about 0-5 ℃, go through about 30 minutes adding triethylamines (0.319g=0.44ml, 3.15mmol).Continued stir about 10 minutes down at 0-5 ℃, mixture is gone through being heated to 20-25 ℃ in about 30 minutes subsequently.Remove by filter the solid of separating out, filter cake t-butyl methyl ether (5ml) drip washing.Stir filtrate, add methyl alcohol (3ml).Described solution concentrates in the about 50 ℃ of following underpressure distillation of outer sheath temperature, up to the resistates that obtains about 10.5ml.Add methyl alcohol (8.5ml), concentrate in the about 50 ℃ of following underpressure distillation of outer sheath temperature once more, up to the resistates that obtains about 10.5ml.Add methyl alcohol (8.5ml) once more, concentrate, up to the resistates that obtains about 10.5ml in the about 50 ℃ of following underpressure distillation of outer sheath temperature.To contain N-[(E)-(R)-1-(3; 4-two chloro-benzyls)-3-((R)-2-oxo-azepan-3-base formamyl)-allyl group]-N-methyl-3; the solution of 5-di-trifluoromethyl-benzamide (12) is cooled to 18-22 ℃, is directly used in next step.
Step 9:N-[(E)-(R)-1-(3,4-two chloro-benzyls)-3-((R)-2-oxo-azepan-3-base ammonia
The base formyl radical)-allyl group]-N-methyl-3,5-di-trifluoromethyl-benzamide semihydrate (13)
Under about 18-22 ℃; to the N-[(E that stirs)-(R)-1-(3; 4-two chloro-benzyls)-3-((R)-2-oxo-azepan-3-base formamyl)-allyl group]-N-methyl-3; add entry (2.6ml) in the methanol solution (10.5ml) of 5-di-trifluoromethyl-benzamide (12), after this begin crystallization.Approximately stir after 10 minutes, under 18-22 ℃, go through and added entry (1ml) in about 20 minutes.Continue down to stir 2 hours at 18-22 ℃.The solid that filtering separation is separated out, filter cake is used water wash (3ml) subsequently with mixture (2ml+1ml) drip washing of first alcohol and water.Solid 30 ℃ of following vacuum-dryings to constant weight; obtain N-[(E)-(R)-1-(3; 4-two chloro-benzyls)-3-((R)-2-oxo-azepan-3-base formamyl)-allyl group]-N-methyl-3; 5-di-trifluoromethyl-benzamide semihydrate (13) [1.6241b; according to (E)-(R)-5-(3; 4-two chloro-phenyl)-4-methylamino-penta-2-olefin(e) acid ((R)-2-oxo-azepan-3-yl)-acid amides (10); theoretical yield 85.5%]; m.p.127-131 ℃; sintering〉123 ℃, MS-ES
+: (MH)
+=624 (
35Cl
2), [α]
D 20=+40.6 ° (methyl alcohol).
Claims (7)
1. the method for a preparation I compound or its solvate or hydrate
Wherein
R is unsubstituted or by 1,2 or 3 phenyl that substituting group replaced, described substituting group is selected from halogen, C
1-C
7-alkyl, trifluoromethyl, hydroxyl and C
1-C
7-alkoxyl group;
R
1Be hydrogen or C
1-C
7-alkyl;
R
2Be hydrogen, C
1-C
7-alkyl or unsubstituted or by 1,2 or 3 phenyl that substituting group replaced, described substituting group is selected from halogen, C
1-C
7-alkyl, trifluoromethyl, hydroxyl and C
1-C
7-alkoxyl group;
R
3For unsubstituted or by 1,2 or 3 phenyl that substituting group replaced, described substituting group is selected from halogen, C
1-C
7-alkyl, trifluoromethyl, hydroxyl and C
1-C
7-alkoxyl group, perhaps R3 is naphthyl, 1H-indol-3-yl or 1-C
1-C
7-alkyl-indol-3-yl; And
R
5Be C
3-C
8-cycloalkyl, D-azepan-2-ketone-3-base or L-azepan-2-ketone-3-base,
Described method comprises the steps:
(a) with the compound of formula II, R wherein
1, R
2, R
3And R
5Such as in this claim above definition, and T is protecting group,
With the compound of alkali reaction formation formula III,
R wherein
1, R
2, R
3And R
5Such as in this claim above definition; With
(b) incite somebody to action wherein R
1, R
2, R
3And R
5As above defined formula III compound in this claim and formula IV compound,
Wherein R is unsubstituted or is selected from halogen, C by 1,2 or 3
1-C
7-alkyl, trifluoromethyl, hydroxyl and C
1-C
7The phenyl that substituting group replaced of-alkoxyl group, and X is halogen,
Reaction forms the compound of formula I in the presence of alkali; And
(c) randomly form required its solvate or hydrate.
2. the method for claim 1, wherein the reductive agent that uses in step (a) is sodium ethylate.
3. method as claimed in claim 1 or 2, wherein R
1, R
2, R
3, R
5Prepare by following steps with T formula II compound as defined in claim 1:
(i) with the compound of formula V,
R wherein
1, R
2And R
3Such as claim 1 definition, and T is protecting group,
In the presence of alkali with 2,2-dimethyl-[1,3] diox-4,6-two reactive ketones form the compound of formula VI
R wherein
1, R
2And R
3Such as claim 1 definition, and T is a protecting group;
(ii) incite somebody to action wherein R
1, R
2And R
3Such as claim 1 definition and T be compound and the methyl alcohol reaction of the formula VI of protecting group, obtain the compound of formula VII,
R wherein
1, R
2And R
3Such as claim 1 definition, and T is a protecting group;
(iii) incite somebody to action wherein R
1, R
2And R
3Such as claim 1 definition and T be the compound reduction of the formula VII of protecting group, form the compound of formula VIII
R wherein
1, R
2And R
3Such as claim 1 definition, and T is a protecting group;
(iv) incite somebody to action wherein R
1, R
2And R
3Such as claim 1 definition and T be the compound hydrolysis of the formula VIII of protecting group, obtain the carboxylic acid of corresponding formula IX
R wherein
1, R
2And R
3Such as claim 1 definition, and T is a protecting group; And
(v) incite somebody to action wherein R
1, R
2And R
3Such as claim 1 definition and T be compound and the reaction of formula X compound of the formula IX of protecting group
H
2N—R
5 X
R wherein
5Be C
3-C
8-cycloalkyl, D-azepan-2-ketone-3-base or L-azepan-2-ketone-3-base.
4. as above-mentioned any described method of claim; its Chinese style I compound is (4R)-4-[N '-methyl-N '-(3; 5-di-trifluoromethyl-benzoyl)-amino]-4-(3, the 4-dichloro benzyl)-but-2-ene acid N-[(R)-ε-Ji Neixianan-3-yl]-the acid amides semihydrate.
5. the method for preparation I compound as claimed in claim 1, this method may further comprise the steps:
(i) with the compound of formula V,
R wherein
1, R
2And R
3Such as claim 1 definition, and T is protecting group,
In the presence of alkali with 2,2-dimethyl-[1,3] diox-4,6-two reactive ketones form the compound of formula VI
R wherein
1, R
2And R
3Such as claim 1 definition, and T is a protecting group;
(ii) incite somebody to action wherein R
1, R
2And R
3Such as claim 1 definition and T be compound and the methyl alcohol reaction of the formula VI of protecting group, obtain the compound of formula VII,
R wherein
1, R
2And R
3Such as claim 1 definition, and T is a protecting group;
(iii) incite somebody to action wherein R
1, R
2And R
3Such as claim 1 definition and T be the compound reduction of the formula VII of protecting group, form the compound of formula VIII
R wherein
1, R
2And R
3Such as claim 1 definition, and T is a protecting group;
(iv) incite somebody to action wherein R
1, R
2And R
3Such as claim 1 definition and T be the compound hydrolysis of the formula VIII of protecting group, obtain the carboxylic acid of corresponding formula IX
R wherein
1, R
2And R
3Such as claim 1 definition, and T is a protecting group;
(v) incite somebody to action wherein R
1, R
2And R
3Such as claim 1 definition and T be compound and the reaction of formula X compound of the formula IX of protecting group
H
2N—R
5 X
R wherein
5Be C
3-C
8-cycloalkyl, D-azepan-2-ketone-3-base or L-azepan-2-ketone-3-base,
Form the compound of formula II
R wherein
1, R
2And R
3Such as claim 1 definition, and T is protecting group, and R
5Be C
3-C
8-cycloalkyl, D-azepan-2-ketone-3-base or L-azepan-2-ketone-3-base;
(vi) purifying R wherein randomly
1, R
2, R
3And R
5Such as claim 1 definition and T be the formula II compound of protecting group;
(vii) incite somebody to action wherein R
1, R
2, R
3And R
5Such as claim 1 definition and T be the formula II compound and the alkali reaction of protecting group, form the compound of formula III
R wherein
1, R
2, R
3And R
5Such as claim 1 definition;
(viii) incite somebody to action wherein R
1, R
2, R
3And R
5As the compound of defined formula III compound of claim 1 and formula IV,
Wherein R is unsubstituted or is selected from halogen, C by 1,2 or 3
1-C
7-alkyl, trifluoromethyl, hydroxyl and C
1-C
7The phenyl that substituting group replaced of-alkoxyl group, and X is halogen,
Reaction forms the compound of formula I, wherein R, R in the presence of alkali
1, R
2, R
3And R
5Such as claim 1 definition; With
(ix) randomly form required solvate or hydrate.
6. basically as the method for any described preparation of embodiment of this paper such as the defined formula I compound of claim 1.
7. basically as any described preparation of embodiment of this paper (4R)-4-[N '-methyl-N '-(3; 5-di-trifluoromethyl-benzoyl)-amino]-4-(3, the 4-dichloro benzyl)-but-2-ene acid N-[(R)-ε-Ji Neixianan-3-yl]-method of acid amides semihydrate.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0607532A GB0607532D0 (en) | 2006-04-13 | 2006-04-13 | Organic compounds |
| GB0607532.9 | 2006-04-13 | ||
| GB0610244A GB0610244D0 (en) | 2006-05-23 | 2006-05-23 | Organic compounds |
| GB0610244.6 | 2006-05-23 | ||
| PCT/EP2007/003213 WO2007118651A1 (en) | 2006-04-13 | 2007-04-11 | Synthesis of acylaminoalkenylene amides useful as substance p antagonists |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101490009A true CN101490009A (en) | 2009-07-22 |
| CN101490009B CN101490009B (en) | 2012-03-21 |
Family
ID=36571849
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2007800126883A Expired - Fee Related CN101490009B (en) | 2006-04-13 | 2007-04-11 | Synthesis of acylaminoalkenylene amides useful as substance P antagonists. |
Country Status (4)
| Country | Link |
|---|---|
| CN (1) | CN101490009B (en) |
| BR (1) | BRPI0711544A2 (en) |
| GB (1) | GB0607532D0 (en) |
| ZA (1) | ZA200807790B (en) |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MY110227A (en) * | 1991-08-12 | 1998-03-31 | Ciba Geigy Ag | 1-acylpiperindine compounds. |
| EP0716077A1 (en) * | 1994-12-08 | 1996-06-12 | Ciba-Geigy Ag | Aromatically substituted omega amino alcanoic acid amides and alcanoic diamides and their use as renine inhibitors |
| AU701560B2 (en) * | 1995-02-22 | 1999-01-28 | Novartis Ag | 1-aryl-2-acylamino-ethane compounds and their use as neurokinin especially neurokinin 1 antagonists |
| MY132550A (en) * | 1996-08-22 | 2007-10-31 | Novartis Ag | Acylaminoalkenylene-amide derivatives as nk1 and nk2 antogonists |
-
2006
- 2006-04-13 GB GB0607532A patent/GB0607532D0/en not_active Ceased
-
2007
- 2007-04-11 BR BRPI0711544-0A patent/BRPI0711544A2/en not_active IP Right Cessation
- 2007-04-11 CN CN2007800126883A patent/CN101490009B/en not_active Expired - Fee Related
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2008
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Also Published As
| Publication number | Publication date |
|---|---|
| BRPI0711544A2 (en) | 2011-11-08 |
| ZA200807790B (en) | 2009-07-29 |
| CN101490009B (en) | 2012-03-21 |
| GB0607532D0 (en) | 2006-05-24 |
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