CN101277931B - Synthetic processes for the preparation of aminocyclohexyl ether compounds - Google Patents
Synthetic processes for the preparation of aminocyclohexyl ether compounds Download PDFInfo
- Publication number
- CN101277931B CN101277931B CN200680021196.6A CN200680021196A CN101277931B CN 101277931 B CN101277931 B CN 101277931B CN 200680021196 A CN200680021196 A CN 200680021196A CN 101277931 B CN101277931 B CN 101277931B
- Authority
- CN
- China
- Prior art keywords
- compound
- general formula
- hydrogen
- group
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 0 **(CC(C1)O*)OC1=* Chemical compound **(CC(C1)O*)OC1=* 0.000 description 10
- VBHQKCBVWWUUKN-KURKYZTESA-N COc1ccc(CCO[C@@H](CCCC2)[C@@H]2N(CC2)C[C@@H]2O)cc1OC Chemical compound COc1ccc(CCO[C@@H](CCCC2)[C@@H]2N(CC2)C[C@@H]2O)cc1OC VBHQKCBVWWUUKN-KURKYZTESA-N 0.000 description 2
- BCJNACBVPVZQPD-IAGOWNOFSA-N C(CO[C@H](CCCC1)[C@@H]1N1CCCC1)C1=CC=[I]C=C1 Chemical compound C(CO[C@H](CCCC1)[C@@H]1N1CCCC1)C1=CC=[I]C=C1 BCJNACBVPVZQPD-IAGOWNOFSA-N 0.000 description 1
- LIYUGICNIDVIPS-VXGBXAGGSA-N CC(C)(C)O[C@H](CCCC1)[C@@H]1N(C)CCN Chemical compound CC(C)(C)O[C@H](CCCC1)[C@@H]1N(C)CCN LIYUGICNIDVIPS-VXGBXAGGSA-N 0.000 description 1
- VBHQKCBVWWUUKN-KSZLIROESA-N COc1ccc(CCO[C@@H](CCCC2)[C@@H]2N(CC2)C[C@H]2O)cc1OC Chemical compound COc1ccc(CCO[C@@H](CCCC2)[C@@H]2N(CC2)C[C@H]2O)cc1OC VBHQKCBVWWUUKN-KSZLIROESA-N 0.000 description 1
- VBHQKCBVWWUUKN-OKZBNKHCSA-N COc1ccc(CCO[C@H](CCCC2)[C@H]2N(CC2)C[C@H]2O)cc1OC Chemical compound COc1ccc(CCO[C@H](CCCC2)[C@H]2N(CC2)C[C@H]2O)cc1OC VBHQKCBVWWUUKN-OKZBNKHCSA-N 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention is directed to stereoselective synthesis of compounds of formula (I) or formula (II) or a pharmaceutically acceptable salt, ester, amide, complex, chelate, clathrate, solvate, polymorph, stereoisomer, metabolite or prodrug thereof; wherein R<3>, R<4> and R<5> are defined herein. Compounds of formula (I) and formula (II) are known to be useful in treating arrhythmias.
Description
Invention field
Present invention relates in general to for example anti--(1R of aminocyclohexyl ether compounds, 2R)-the stereoselectivity preparation method of aminocyclohexyl ether compounds and/or anti--(1S, 2S)-aminocyclohexyl ether compounds and the different intermediates, substrate and the steric isomer that relate to.In addition, the present invention relates to for example stereoselectivity preparation method of suitable-(1R, 2S)-aminocyclohexyl ether compounds and/or suitable-(1S, 2R)-aminocyclohexyl ether compounds of aminocyclohexyl ether compounds.Compound by method preparation of the present invention can be used for treating medical conditions state or illness, comprises for example irregular pulse, such as atrium irregular pulse and ventricular arrhythmia.
Background of invention
Irregular pulse is departing from of the normal rhythm of heartbeat, and usually represents the final product of unusual ionic channel structure, number or function.Known atrial arrhythmia and the ventricular arrhythmia of existing.It is the ventricular arrhythmia hypotype that is called as ventricular fibrillation (VF) that irregular pulse causes deadly major cause.Conservative estimation shows, only in the U.S., annually surpasses 1,000,000 American and can suffer from crown outbreak (being defined as myocardial infarction or fatal coronary heart disease) first or that repeat.650,000 be first heart attack approximately in these individualities, 450,000 for again showing effect.Experiencing among the people of these outbreaks approximately, 1/3rd result is dead.The individuality in every year at least 250,000 is dead within 1 hour of symptom occurring and before obtaining enough medical rescues because of coronary heart disease.These are the sudden death that caused by asystole, and asystole is normally caused by ventricular fibrillation.
Auricular fibrillation (AF) is modal irregular pulse in the clinical practice, and is reason (PritchettE.L., N.Engl.J.Med.327 (14): 1031Oct.1,1992, the discussion 1031-2 that falls ill in many individualities; Kannel and Wolf, Am.HeartJ.123 (1): 264-7Jan.1992).Its popular may increasing with the aging of population, and estimate that the patient above 60 years old of 3-5% suffers from AF (KannelW.B., AbbotR.D., SavageD.D., McNamaraP.M., N.Engl.J.Med.306 (17): 1018-22,1982; WolfP.A., AbbotR.D., KannelW.B.Stroke.22 (8): 983-8,1991).Although AF seldom is fatal, it can weaken heart body and be major cause (Hinton R.C, the KistlerJ.P. of apoplexy, FallonJ.T., Friedlich A.L., Fisher CM., American Journal of Cardiology40 (4): 509-13,1977; Wolf P.A., Abbot R.D., Kannel W.B., Archives ofInternal Medicine147 (9): 1561-4,1987; Wolf P.A., Abbot R.D., KannelW.B.Stroke.22 (8): 983-8,1991; Cabin H.S., Clubb K.S., Hall C., Perlmutter R.A., Feinstein A.R., American Journal of Cardiology65 (16): 1112-6,1990).
The disclosed patent application WO99/50225 of PCT and WO2004/099137 and United States Patent (USP) disclose aminocyclohexyl ether compounds the 7th, 057, No. 053 and can be used for treating irregular pulse.Found that wherein disclosed some compound is significantly effective in treating and/or preventing AF.Yet, in these patent applications and patent and the described synthetic method right and wrong in other places stereoselective, and cause the mixture of steric isomer.As active pharmaceutical compounds, expect that usually drug molecule is the pure form of basic stereoisomerism.If must after multistep is synthetic, from the mixture of steric isomer, separate correct isomer, it may not feasible or the saving cost.Therefore, the method for the preparation of the pure trans aminocyclohexyl ether compounds of basic stereoisomerism need to be developed in this area.
Summary of the invention
The present invention relates to the intermediate of the stereoselectivity novelty synthetic and that wherein prepare of some aminocyclohexyl ether compounds.The invention still further relates to concrete aminocyclohexyl ether compounds.
Therefore, an aspect of of the present present invention relates to the preparation method of general formula (I) compound, its single stereoisomers or its mixture or the acceptable salt of its medicine, ester, acid amides, title complex, inner complex, inclusion compound, solvate, polymorphic form, steric isomer, metabolite or prodrug:
Wherein:
R
3, R
4And R
5Be independently bromine, chlorine, fluorine, carboxyl, hydrogen, hydroxyl, methylol, sulfonyl methane amino, nitro, cyano group, sulfamyl, trifluoromethyl ,-CHF
2,-SO
2N (R
8) R
9,-OCF
3, C
2-C
7Alkylacyloxy, C
1-C
6Alkyl, C
1-C
6-oxyl, C
7-C
12Virtue-oxyl, C
2-C
7Hydrocarbon carbonyl oxygen, C
1-C
6Sulfo-alkyl, aryl or-N (R
6) R
7(preferred R
3, R
4And R
5Be hydrogen, hydroxyl or C independently
1-C
6-oxyl; But R
3, R
4And R
5Can not all be hydrogen simultaneously); And
R
6, R
7, R
8And R
9All be independently selected from hydrogen, ethanoyl, methane sulfonyl or C 2R-or 3R-acetoxyl group-N-(2R-benzyloxy cyclohexyl) succsinic acid (7a)/(8a) (1.40g, 3.85mmol) are dissolved in Acetyl Chloride 98Min. (15mL).The homogeneous solution that obtains was refluxed 45 minutes at 60 ℃.Removing volatiles under vacuum, and the resistates that obtains is further dry under high vacuum, obtain transparent faint yellow soup compound (3R)-1-((1R, 2R)-2-benzyloxy hexamethylene-1-yl)-2,5-dioxy pyrrolidin-3-yl acetic ester (3a); MS (ES+) 346.1[M+H]
+, 363.2[M+H
2O]
+, 368.1[M+Na]
+ 1H-NMR (400MHz, CDCl
3) δ 1.24-1.32 (m, 3H), 1.66-1.80 (m, 3H), (2.10 s, 3H), 2.12-2.29 (m, 2H), (2.40-2.45 m, 1H), 2.88-2.96 (m, 1H), (3.95-4.07 m, 2H), 4.23-4.27 (m, 1H), (4.57-4.61 m, 1H), 5.05 (br s, 1H), (7.18-7.20 m, 2H), 7.23-7.31 (m, 3H);
13C-NMR (100MHz, CDCl
3) δ 20.58,23.90,24.89,27.87,31.32,35.39,56.12,66.78,70.54,75.64,127.50,128.27,128.99,138.83,169.71,173.33,173.49.
Preparation 3
Each R wherein
2aBe O or H
2, at least one R wherein
2aBe O, R is H, C
2-C
5Acyl group or oxygen protecting group, and R
3, R
4And R
5As hereinbefore defined.Described suitable reaction conditions is so that in a single day general formula (4) compound reacts with general formula (5) compound, and the trans relative configuration of the oh group on 1 carbon of general formula (4) compound just is retained on 1 carbon of general formula (6) compound;
B) general formula (6) compound is reduced to form general formula (I) compound under suitable condition.
The method can also be included in the deprotection steps before general formula (4) compound and the reaction of general formula (5) compound, and wherein said deprotection steps comprises general formula (3) compound:
Each R wherein
2aBe O or H
2, at least one R wherein
2aBe O, R
1Be oxygen protecting group (being preferably the optional benzyl that replaces), and R is H, C
2-C
5Acyl group or oxygen protecting group (are preferably C
2-C
5Acyl group),
Under suitable deprotection condition, process to form general formula mentioned above (4) compound.
The method can also comprise cyclisation step to form general formula (3) compound, and wherein said cyclisation step comprises the mixture reaction that makes under suitable condition general formula (7) compound or general formula (8) compound or general formula (7) compound and general formula (8) compound:
Each R wherein
1Be independently oxygen protecting group (being preferably the optional benzyl that replaces), each R
2aBe O or H
2, and R is H, C
2-C
5Acyl group or oxygen protecting group (are preferably C
2-C
5Acyl group),
To form general formula as indicated above (3) compound.
The method can also comprise condensation step to form the mixture of general formula (7) compound or general formula (8) compound or general formula (7) compound and general formula (8) compound, and wherein said condensation step comprises makes general formula (1) compound:
R wherein
1Be oxygen protecting group (being preferably the optional benzyl that replaces),
With general formula (2a) compound:
Each R wherein
2aBe O or H
2, at least one R in its formula of (2a) compound
2aBe O, R is H, C
2-C
5Acyl group or oxygen protecting group (preferred C
2-C
5Acyl group),
Under suitable condition reaction is to form the mixture of general formula as indicated above (7) compound or general formula (8) compound or general formula (7) compound and general formula (8) compound.
Another aspect of the present invention relates to the preparation method of general formula (I) compound, its single stereoisomers or its mixture or the acceptable salt of its medicine, ester, acid amides, title complex, inner complex, inclusion compound, solvate, polymorphic form, steric isomer, metabolite or prodrug:
Wherein:
R
3, R
4And R
5Be independently bromine, chlorine, fluorine, carboxyl, hydrogen, hydroxyl, methylol, sulfonyl methane amino, nitro, cyano group, sulfamyl, trifluoromethyl ,-CHF
2,-SO
2N (R
8) R
9,-OCF
3, C
2-C
7Alkylacyloxy, C
1-C
6Alkyl, C
1-C
6-oxyl, C
7-C
12Virtue-oxyl, C
2-C
7Hydrocarbon carbonyl oxygen, C
1-C
6Sulfo-alkyl, aryl or-N (R
6) R
7(preferred R
3, R
4And R
5Be hydrogen, hydroxyl or C independently
1-C
6-oxyl; But R
3, R
4And R
5Can not all be hydrogen simultaneously); And
R
6, R
7, R
8And R
9All be independently selected from hydrogen, ethanoyl, methane sulfonyl or C
1-C
6Alkyl;
Described method comprises:
A) with formula (1a) compound:
With general formula (2a) compound:
Under suitable condensation condition, react, to form product;
B) with a) product and general formula (5) compound:
Wherein Q is leavings group, and R
3, R
4And R
5As hereinbefore defined, under suitable ether coupling condition, react to form product;
C) with b) product under suitable cyclisation conditions, react, to form general formula (6) compound:
Each R wherein
2aBe O or H
2, at least one R wherein
2aBe O, R is H, C
2-C
5Acyl group or oxygen protecting group (are preferably C
2-C
5And R acyl group),
3, R
4And R
5As hereinbefore defined; And
D) general formula (6) compound is reduced under suitable condition, to form general formula as indicated above (I) compound.
Above-mentioned steps product a) can comprise the mixture of general formula (9) compound, general formula (10) compound or general formula (9) compound and general formula (10) compound:
Each R wherein
2aBe O or H
2, and R is H, C
2-C
5Acyl group or oxygen protecting group (preferred C
2-C
5Acyl group).
Above-mentioned steps b) product can comprise the mixture of general formula (11) compound, general formula (12) compound or general formula (11) compound and general formula (12) compound:
Each R wherein
2aBe O or H
2, R is H, C
2-C
5Acyl group or oxygen protecting group (are preferably C
2-C
5Acyl group) and R
3, R
4And R
5As hereinbefore defined.
Another aspect of the present invention relates to the preparation method of general formula (I) compound, its single stereoisomers or its mixture or the acceptable salt of its medicine, ester, acid amides, title complex, inner complex, inclusion compound, solvate, polymorphic form, steric isomer, metabolite or prodrug:
Wherein:
R
3, R
4And R
5Be independently bromine, chlorine, fluorine, carboxyl, hydrogen, hydroxyl, methylol, sulfonyl methane amino, nitro, cyano group, sulfamyl, trifluoromethyl ,-CHF
2,-SO
2N (R
8) R
9,-OCF
3, C
2-C
7Alkylacyloxy, C
1-C
6Alkyl, C
1-C
6-oxyl, C
7-C
12Virtue-oxyl, C
2-C
7Hydrocarbon carbonyl oxygen, C
1-C
6Sulfo-alkyl, aryl or-N (R
6) R
7(preferred R
3, R
4And R
5Be hydrogen, hydroxyl or C independently
1-C
6-oxyl; But R
3, R
4And R
5Can not all be hydrogen simultaneously); And
R
6, R
7, R
8And R
9All be independently selected from hydrogen, ethanoyl, methane sulfonyl or C
1-C
6Alkyl;
Described method comprises:
A) with general formula (17) compound:
R wherein
3, R
4And R
5As hereinbefore defined,
With general formula (2a2) compound:
Wherein R is H, C
2-C
5Acyl group or oxygen protecting group (are preferably C
2-C
5Acyl group), under suitable condensation condition, react, to form general formula (6b) compound:
Wherein R is H, C
2-C
5Acyl group or oxygen protecting group (being preferably the optional benzyl that replaces), and R
3, R
4And R
5As hereinbefore defined; And
B) general formula (6b) compound is reduced under suitable condition, to form above-mentioned general formula (I) compound.
The method can also comprise the nucleophilic substitution step forming general formula (17) compound, and wherein said nucleophilic substitution step comprises with trinitride processes general formula (16) compound under suitable nucleophilic substitution and follow-up reductive condition:
Wherein-OR ' is active leavings group (being preferably the optional hydrocarbyl sulfonic ester that replaces or the optional aromatic yl sulphonate that replaces), and R
3, R
4And R
5As hereinbefore defined,
To form above-mentioned general formula (17) compound.
The method can also comprise preparation process to form general formula (16) compound, and wherein said preparation process comprises makes general formula (15) compound:
R wherein
3, R
4And R
5As hereinbefore defined,
Under suitable condition with active reagent (being preferably the optional alkyl sulfonic acid halide that replaces or the optional aryl sulfonyl halide that replaces) reaction, to form above-mentioned general formula (16) compound.
The method can also comprise the asymmetric reduction step to form compound (15), and wherein said asymmetric reduction step is included in and processes general formula (14) compound under asymmetric reduction/hydrogenation conditions:
R wherein
3, R
4And R
5As hereinbefore defined,
To form above-mentioned general formula (15) compound.
The method can also comprise etherification step to form general formula (14) compound, and wherein said etherification step comprises formula (13) compound:
With general formula (5b) compound:
R wherein
3, R
4And R
5As hereinbefore defined,
Process under suitable condition, to form above-mentioned general formula (14) compound.
Another aspect of the present invention relates to the preparation method of general formula (II) compound, its single stereoisomers or its mixture or the acceptable salt of its medicine, ester, acid amides, title complex, inner complex, inclusion compound, solvate, polymorphic form, steric isomer, metabolite or prodrug:
Wherein:
R
3, R
4And R
5Be independently bromine, chlorine, fluorine, carboxyl, hydrogen, hydroxyl, methylol, sulfonyl methane amino, nitro, cyano group, sulfamyl, trifluoromethyl ,-CHF
2,-SO
2N (R
8) R
9,-OCF
3, C
2-C
7Alkylacyloxy, C
1-C
6Alkyl, C
1-C
6-oxyl, C
7-C
12Virtue-oxyl, C
2-C
7Hydrocarbon carbonyl oxygen, C
1-C
6Sulfo-alkyl, aryl or-N (R
6) R
7(preferred R
3, R
4And R
5Be hydrogen, hydroxyl or C independently
1-C
6-oxyl; But R
3, R
4And R
5Can not all be hydrogen simultaneously); And
R
6, R
7, R
8And R
9All be independently selected from hydrogen, ethanoyl, methane sulfonyl or C
1-C
6Alkyl;
Described method comprises:
A) with general formula (20) compound:
Each R wherein
2aBe O or H
2, at least one R in its formula of (20) compound
2aBe O, and R is H, C
2-C
5Acyl group or oxygen protecting group (are preferably C
2-C
5Acyl group),
Under suitable reaction conditions, react with general formula (5) compound:
R wherein
3, R
4And R
5As hereinbefore defined, and Q is leavings group, to form general formula (21) compound:
Each R wherein
2aBe O or H
2, at least one R wherein
2aBe O, R is H, C
2-C
5Acyl group or oxygen protecting group, and R
3, R
4And R
5As hereinbefore defined.Described suitable reaction conditions makes general formula (20) compound in case react with general formula (5) compound, and the trans relative configuration of the oh group on 1 carbon of general formula (20) compound just is retained on 1 carbon of general formula (21) compound;
B) general formula (21) compound is reduced to form general formula (II) compound under suitable condition.
The method can also be included in the deprotection steps before general formula (20) compound and the reaction of general formula (5) compound, and wherein said deprotection steps comprises general formula (19) compound:
Each R wherein
2aBe O or H
2, at least one R wherein
2aBe O, R
1Be oxygen protecting group (being preferably the optional benzyl that replaces), and R is H, C
2-C
5Acyl group or oxygen protecting group (are preferably C
2-C
5Acyl group),
Under suitable deprotection condition, process to form general formula mentioned above (20) compound.
The method can also comprise cyclisation step to form general formula (19) compound, and wherein said cyclisation step comprises the mixture that makes general formula (23) compound or general formula (24) compound or general formula (23) compound and general formula (24) compound:
Each R wherein
1Be independently oxygen protecting group (being preferably the optional benzyl that replaces), each R
2aBe O or H
2, and R is H, C
2-C
5Acyl group or oxygen protecting group (are preferably C
2-C
5Acyl group),
React under suitable condition to form above-mentioned general formula (19) compound.
The method can also comprise condensation step to form the mixture of general formula (23) compound or general formula (24) compound or general formula (23) compound and general formula (24) compound, and wherein said condensation step comprises makes general formula (18) compound:
R wherein
1Be oxygen protecting group (being preferably the optional benzyl that replaces),
With general formula (2a) compound:
Each R wherein
2aBe O or H
2, at least one R wherein
2aBe O, R is H, C
2-C
5Acyl group or oxygen protecting group (are preferably C
2-C
5Acyl group),
Under suitable condition reaction is to form the mixture of above-mentioned general formula (23) compound or general formula (24) compound or general formula (23) compound and general formula (24) compound.
Another aspect of the present invention relates to the preparation method of general formula (II) compound, its single stereoisomers or its mixture or the acceptable salt of its medicine, ester, acid amides, title complex, inner complex, inclusion compound, solvate, polymorphic form, steric isomer, metabolite or prodrug:
Wherein:
R
3, R
4And R
5Be independently bromine, chlorine, fluorine, carboxyl, hydrogen, hydroxyl, methylol, sulfonyl methane amino, nitro, cyano group, sulfamyl, trifluoromethyl ,-CHF
2,-SO
2N (R
8) R
9,-OCF
3, C
2-C
7Alkylacyloxy, C
1-C
6Alkyl, C
1-C
6-oxyl, C
7-C
12Virtue-oxyl, C
2-C
7Hydrocarbon carbonyl oxygen, C
1-C
6Sulfo-alkyl, aryl or-N (R
6) R
7(preferred R
3, R
4And R
5Be hydrogen, hydroxyl or C independently
1-C
6-oxyl; But R
3, R
4And R
5Can not all be hydrogen simultaneously); And
R
6, R
7, R
8And R
9All be independently selected from hydrogen, ethanoyl, methane sulfonyl or C
1-C
6Alkyl;
Described method comprises:
A) with formula (22) compound:
With general formula (2a) compound:
Under suitable condensation condition, react, to form product;
B) with a) product and general formula (5) compound:
Wherein Q is leavings group, and R
3, R
4And R
5As hereinbefore defined, under suitable ether coupling condition, react to form product;
C) make b) product under suitable cyclisation conditions, react, to form general formula (21) compound:
Each R wherein
2aBe O or H
2, R is H, C
2-C
5Acyl group or oxygen protecting group (are preferably C
2-C
5And R acyl group),
3, R
4And R
5As hereinbefore defined; And
D) general formula (21) compound is reduced under suitable condition, to form above-mentioned general formula (II) compound.
Above-mentioned steps product a) can comprise the mixture of general formula (25) compound, general formula (26) compound or general formula (25) compound and general formula (26) compound:
Each R wherein
2aBe O or H
2, and R is H, C
2-C
5Acyl group or oxygen protecting group.
Above-mentioned steps b) product can comprise the mixture of general formula (27) compound, general formula (28) compound or general formula (27) compound and general formula (28) compound:
Each R wherein
2aBe O or H
2, R is H, C
2-C
5Acyl group or oxygen protecting group, and R
3, R
4And R
5As hereinbefore defined.
Another aspect of the present invention relates to the preparation method of general formula (II) compound, its single stereoisomers or its mixture or the acceptable salt of its medicine, ester, acid amides, title complex, inner complex, inclusion compound, solvate, polymorphic form, steric isomer, metabolite or prodrug:
Wherein:
R
3, R
4And R
5Be independently bromine, chlorine, fluorine, carboxyl, hydrogen, hydroxyl, methylol, sulfonyl methane amino, nitro, cyano group, sulfamyl, trifluoromethyl ,-CHF
2,-SO
2N (R
8) R
9,-OCF
3, C
2-C
7Alkylacyloxy, C
1-C
6Alkyl, C
1-C
6-oxyl, C
7-C
12Virtue-oxyl, C
2-C
7Hydrocarbon carbonyl oxygen, C
1-C
6Sulfo-alkyl, aryl or-N (R
6) R
7(preferred R
3, R
4And R
5Be hydrogen, hydroxyl or C independently
1-C
6-oxyl; But R
3, R
4And R
5Can not all be hydrogen simultaneously); And
R
6, R
7, R
8And R
9All be independently selected from hydrogen, ethanoyl, methane sulfonyl or C
1-C
6Alkyl;
Described method comprises:
A) with general formula (33) compound:
R wherein
3, R
4And R
5As hereinbefore defined,
With general formula (2a2) compound:
Wherein R is H, C
2-C
5Acyl group or oxygen protecting group (are preferably C
2-C
5Acyl group), under suitable condensation condition, react, to form general formula (21b) compound:
Wherein R is H, C
2-C
5Acyl group or oxygen protecting group (preferred C
2-C
5And R acyl group),
3, R
4And R
5As hereinbefore defined; And
B) general formula (6b) compound is reduced under suitable condition, to form above-mentioned general formula (II) compound.
The method can comprise the nucleophilic substitution step, and forming general formula (33) compound, wherein said nucleophilic substitution step is included under suitable nucleophilic substitution and the follow-up reductive condition and processes general formula (32) compound with trinitride:
Wherein-OR ' is active leavings group (being preferably the optional hydrocarbyl sulfonic ester that replaces or the optional aromatic yl sulphonate that replaces), and R
3, R
4And R
5As hereinbefore defined,
To form above-mentioned general formula (33) compound.
The method can also comprise makes general formula (31) compound:
R wherein
3, R
4And R
5It is as indicated above,
With under suitable condition reaction of active reagent (being preferably the optional alkyl sulfonic acid halide that replaces or the optional aryl sulfonyl halide that replaces), to form above-mentioned general formula (32) compound.
The method can also comprise reduction step to form compound (31), and wherein said reduction step comprises processes general formula (14) compound under suitable condition:
R wherein
3, R
4And R
5As hereinbefore defined,
To form above-mentioned general formula (31) compound.
The method can also comprise etherification step to form general formula (14) compound, and wherein said etherification step comprises uses general formula (5b) compound under suitable condition:
R wherein
3, R
4And R
5As hereinbefore defined,
Processing formula (13) compound:
To form above-mentioned general formula (14) compound.
All aforesaid methods can also comprise the acid-adducting salt that forms general formula (I) compound or general formula (II) compound.
Another aspect of the present invention relates to method disclosed herein synthetic intermediate and compound.
Another aspect of the present invention relates to general formula (I) compound.
Detailed description of the present invention
Stereoselectivity preparation method as indicated above, as to the present invention relates to above at (I) compound of the general formula described in the summary of the invention and general formula (II) compound.
By helping to understand the present invention with reference to hereinafter definition with to the explanation of convention used herein.
General formula (I) compound has ether oxygen atom 1 of cyclohexane ring, and has amine nitrogen atom 2 of cyclohexane ring, and number according to the respective sequence as shown in following structure (A) other position:
In the above-mentioned general formula, from cyclohexane ring to 1-oxygen and the chemical bond of 2-nitrogen-atoms be arranged as trans relation.Therefore, for the trans-stereoisomer of general formula (I) compound, the substituent stereochemistry of the amine of cyclohexane ring and ether is (R, R)-trans or (S, S)-trans.
According to the practice of standard chemical document description and employed such as this specification sheets, solid line saturated bond as shown in above-mentioned structure (A) and the dotted line saturated bond as shown in above-mentioned structure (A) represent substituting group, in this case, amine and ether substituting group are transconfiguration with respect to the plane of cyclohexane ring.
According to the practice of standard chemical document description and employed such as this specification sheets, such as following structure, (Aa) the wedge shape saturated bond shown in represents the substituting group of being combined with cyclohexane ring by this key, in this case, the ether substituting group is above the cyclohexane ring plane of the paper shown in the two-dimensional representation method, and as following structure, (Aa) the dotted line webge groove shown in represents the substituting group of being combined with cyclohexane ring by this key, in this case, the amine substituting group is below the cyclohexane ring plane of the represented paper of two-dimensional representation method
General formula (II) compound has ether oxygen atom 1 of cyclohexane ring, and has amine nitrogen atom 2 of cyclohexane ring, and number according to the respective sequence as shown in following structure (B) other position:
In the above-mentioned general formula, from cyclohexane ring to 1-oxygen and the chemical bond of 2-nitrogen-atoms be arranged as cis relation.Therefore, for the cis-stereoisomer of general formula (II) compound, the substituent stereochemistry of the amine of cyclohexane ring and ether is (R, S)-cis or (S, R)-cis.
According to the practice of standard chemical document description and employed such as this specification sheets, two solid line saturated bonds as shown in above-mentioned structure (B) represent substituting group, and in this case, amine and ether substituting group are cis-configuration with respect to the plane of cyclohexane ring.
According to the practice of standard chemical document description and employed such as this specification sheets, such as following structure, (Ba) the wedge shape saturated bond shown in represents the substituting group of being combined with cyclohexane ring by this key, in this case, ether and amine substituting group are above the cyclohexane ring plane with the represented paper of two-dimensional representation method, and as following structure, (Bb) the dotted line webge groove shown in represents the substituting group of being combined with cyclohexane ring by this key, in this case, ether and amine substituting group are below the cyclohexane ring plane with the represented paper of two-dimensional representation method
According to the practice of standard chemical document description and employed such as this specification sheets, the wavy key table as shown in following general formula (2a2) compound shows substituting group, and in this case ,-OR substituting group is above the cyclohexane ring or below cyclohexane ring:
In general formula described herein, the key that is connected with substituting group and/or the key that molecule fragment is connected with the rest part of compound can be represented as in ring structure insert one or more keys.This shows that this key can be connected on arbitrary atom of makeup ring structure, as long as can have hydrogen atom on this atom.Specific position in structure does not have specific substituting group, and then there is hydrogen in this position.For example, general formula (I) compound contains group (C):
Wherein said group (C) is intended to contain following radicals: wherein arbitrarily annular atoms can be replaced by hydrogen or by arbitrary R
3, R
4Or R
5Replace, but each R
3, R
4And R
5Occur once and only occur once at ring.Not by R
3, R
4Or R
5Monobasic annular atoms replaced by hydrogen.
The compounds of this invention contains at least two unsymmetrical carbons, and therefore exists as enantiomer and diastereomer.For the present invention, wording diastereomer and diastereomer and relational language be equal to and be interchangeable.Except as otherwise noted, the present invention includes all enantiomerisms and the diastereo-isomerism form of general formula (I) compound and general formula (II) compound aminocyclohexyl ether.Comprise the mixture of pure stereoisomers, enantiomer and/or diastereomer and the mixture of the different compounds of the present invention among the present invention.Therefore, unless indicate specific steric isomer, enantiomer or diastereomer, general formula (I) compound and general formula (II) compound can racemic modifications, racemize or diastereo-isomerism form of mixtures exist, and exist with independent diastereomer or enantiomeric forms, all isomeric form include in the present invention.For the present invention, racemic modification, diastereo-isomerism or racemic mixture do not mean that and only are 50: 50 mixtures of steric isomer.The enantiomer of the steric isomer that also is intended to comprise that other is rich in different ratios or the mixture of diastereomer.Except as otherwise noted, wording " basic stereoisomerism pure " is often referred to described in the general structure of described compound or illustrative those unsymmetrical carbons.
The definition of stereoisomeric purity (or optical purity or chiral purity) and relational language and measuring method (such as opticity, circular dichroism etc.) thereof be as known in the art (referring to, such as E.L Elieland S.H.Wilen, in Stereochemistry of Organic Compounds (stereochemistry of organic compound); John Wiley﹠amp; Sons:New York, 1994 reach the reference of wherein quoting).Wording " basic stereoisomerism is pure " is often referred to a kind of steric isomer in the sample (such as enantiomer or diastereomer) with respect to the enrichment of another steric isomer, and this causes the chirality enrichment of sample and optically active to increase.Enantiomer is each other one of mirror image and a pair of molecule that can not superpose.They are " mirror image " steric isomers.Diastereomer is often referred to not the each other steric isomer of mirror image.Term enantiomerism excessive (ee) and diastereo-isomerism excessive (de) are commonly used to refer to the stereoisomeric purity (or optical purity or chiral purity) of the compound sample paid close attention to.Its definition and measuring method are well known in the art, and can be at for example E.L.Elieland S.H.Wilen, in Stereochemistry of Organic Compounds (stereochemistry of organic compound); John Wiley﹠amp; Sons:New York, 1994 and the reference wherein quoted in find." stereoselectivity preparation " refers to that preparation has the compound of enantiomerism excessive (ee) or diastereo-isomerism excessive (de).
For the present invention, consider approximately 50% to approximately 100% enantiomerism excessive (ee) or diastereo-isomerism excessive (de).Preferred enantiomerism excessive (ee) or diastereo-isomerism excessive (de) are approximately 60% to approximately 100%.Another preferred enantiomerism excessive (ee) or diastereo-isomerism excessive (de) are approximately 70% to approximately 100%.Preferred enantiomerism excessive (ee) or diastereo-isomerism excessive (de) are approximately 80% to approximately 100%.Another preferred enantiomerism excessive (ee) or diastereo-isomerism excessive (de) are approximately 85% to approximately 100%.Even preferred enantiomerism excessive (ee) or diastereo-isomerism excessive (de) are approximately 90% to approximately 100%.Another even preferred enantiomerism excessive (ee) or diastereo-isomerism excessive (de) are approximately 95% to approximately 100%.Should be appreciated that, wording " approximately 50% to approximately 100% " includes but not limited to all possible percentage ratio and mark in 50% to 100%.Similarly, wording " approximately 60% to approximately 100% " includes but not limited to all possible percentage ratio and mark in 60% to 100%; Wording " approximately 70% to approximately 100% " includes but not limited to all possible percentage ratio and mark in 70% to 100%; Wording " approximately 80% to approximately 100% " includes but not limited to all possible percentage ratio and mark in 80% to 100%; Wording " approximately 85% to approximately 100% " includes but not limited to all possible percentage ratio and mark in 85% to 100%; Wording " approximately 90% to approximately 100% " includes but not limited to all possible percentage ratio and mark in 90% to 100%; Wording " approximately 95% to approximately 100% " includes but not limited to all possible percentage ratio and mark in 95% to 100%.
As an example, but do not limit above-mentioned rule, design has the compound of following general formula 4 ':
It comprises at least three chiral centres (the cyclohexyl carbon that is connected with 1 oxygen, the cyclohexyl carbon that is connected with 2 nitrogen and the pyrrolidyl carbon that is connected with 3 ' oxygen), and therefore has the independent trans-stereoisomer of at least four classes, i.e. (1R, 2R)-2-[(3R)-hydroxyl pyrrolidine base]-1-(R
3-, R
4-and R
5The benzene oxyethyl group of-replacement) hexanaphthene; (1R, 2R)-2-[(3S)-hydroxyl pyrrolidine base]-1-(R
3-, R
4-and R
5The benzene oxyethyl group of-replacement) hexanaphthene; (1S, 2S)-2-[(3R)-hydroxyl pyrrolidine base]-1-(R
3-, R
4-and R
5The benzene oxyethyl group of-replacement) hexanaphthene; And (1S, 2S)-2-[(3S)-hydroxyl pyrrolidine base]-1-(R
3-, R
4-and R
5The benzene oxyethyl group of-replacement) hexanaphthene; Unless and in this specification sheets, express in addition, have the compound of following general formula:
Mean composition, its composition that comprises is one of the possible pure enantiomerism of described compound or diastereo-isomerism form or is arbitrarily two or more pure enantiomerism or the mixture of diastereo-isomerism form, and wherein said mixture can comprise enantiomerism or the diastereo-isomerism form of arbitrary ratio, any amount.
As an example, but do not limit above-mentioned rule, unless in this specification sheets, express in addition, be designed to have compound name and be called (1R, 2R)/(1S, 2S)-2-[(3R)-the hydroxyl pyrrolidine base]-1-(3,4-dimethoxy benzene oxyethyl group) compound of hexanaphthene means composition, its composition that comprises is the pure diastereomeric form formula of two kinds of described compound (i.e. (1R, 2R)-2-[(3R)-the hydroxyl pyrrolidine base]-1-(3,4-dimethoxy benzene oxyethyl group) hexanaphthene or (1S, 2S)-2-[(3R)-the hydroxyl pyrrolidine base]-1-(3,4-dimethoxy benzene oxyethyl group) hexanaphthene) one or both, or be the mixture of described two kinds of pure diastereomeric form formulas, wherein said mixture can comprise described two kinds of diastereomers of any correlative.
Wording " the independent existence " is intended to expression (i) when any variable occurs surpassing one time in the compounds of this invention, the definition when this variable occurs at every turn is independent of its definition when other occurs at every turn; And any that (ii) select two different variablees is (such as R
3, R
4And R
5Group in R
3) feature, and do not consider the feature of other member in this group.Yet, to only have when the compound of valency standard rule is not violated in the combination of substituting group and/or variable, such combination is only permission.
Before some chemical group of name contracted notation " C is arranged in this article
x-C
y", wherein x and y represent respectively the less and more carbon atom number that exists in the described chemical group.C for example
1-C
8Alkyl describe have 1 to 8 carbon atom altogether such as defined hydrocarbyl group hereinafter, and C
7-C
12Aryl describe have 7 to 12 carbon atoms altogether such as defined aryl group hereinafter.Sometimes before some chemical group of name contracted notation " C is arranged in this article
z", wherein z represents the total number of carbon atoms of existing in the described chemical group.Carbon sum in the contracted notation does not comprise the carbon that may exist in the substituting group of described group.
According to the present invention and used herein, unless other clear, following term is defined as has following connotation:
" acid-adducting salt " is often referred to, but be not limited to, the biological effectiveness of reservation free alkali and character, suitable and those salt that use mineral acid or organic acid to form in biology or other side, described mineral acid is such as but not limited to hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid etc. or acceptable Lewis acid, described organic acid is such as but not limited to acetic acid, propionic acid, oxyacetic acid, pyruvic acid, oxalic acid, toxilic acid, propanedioic acid, succsinic acid, fumaric acid, tartrate, citric acid, phenylformic acid, styracin, amygdalic acid, methylsulfonic acid, ethyl sulfonic acid, tosic acid, Whitfield's ointment etc., and include but not limited to that those are for example at " Handbook of Pharmaceutical Salts; Properties; Selection; and Use (drug salts handbook; character; select and purposes) ", P.Heinrich Stahl and Camille G.Wermuth (Eds.), Published by VHCA (Switzerland) and Wiley-VCH (FRG), the acid-adducting salt described in 2002.
" acyl group " refers to contain side chain or the unbranched hydrocarbon fragment for acyl group-(the C=O)-group given number carbon atom, terminal.Example comprises ethanoyl (Ac) [CH
3C (=O)-, be C
2Acyl group] and propionyl [CH
3CH
2C (=O)-, be C
3Acyl group].
" alkylacyloxy " refers to the ester substituting group, and wherein non-ketonic oxygen is the point with minute sub-connection.Example comprises propionyloxy [(CH
3CH
2C (=O)-and O-, be C
3Alkylacyloxy] and acetoxyl group [CH
3C (=O)-and O-, be C
2Alkylacyloxy].
" aromatic hydrocarbons acyloxy " refers to the ester substituting group, and wherein non-ketonic oxygen is the point with minute sub-connection, and this ester substituting group also comprises the alkylene group, and one of them tie point is connected with aromatic yl group.The example of aromatic hydrocarbons acyloxy group is C
6H
5CH
2C (=O)-and O-, be C
8Aromatic hydrocarbons acyloxy group.
"-oxyl " refers to the oxygen (O) that replaced by hydrocarbyl group-atom, and for example,-oxyl can include but not limited to methoxyl group, and it can also be expressed as-OCH
3,-OMe or C
1-oxyl.
"-oxyl alkyl " refers to the alkylene group that replaced by the-oxyl group.For example, 2-methoxy ethyl [CH
3OCH
2CH
2-], 1-methoxy ethyl [CH
3CH (OCH
3)-] and ethoxyl methyl (CH
3CH
2OCH
2-] be C
3The-oxyl alkyl.
" fragrant-oxyl " refers to the oxygen (O) that replaced by the aryl group-atom.The example of virtue-oxyl group is C
6H
5CH
2O-is C
7Virtue-oxyl group.
" hydrocarbon carbonyl oxygen " refers to the ester substituting group, and wherein carbonyl carbon is the point with minute sub-connection.Example comprises ethoxy carbonyl [CH
3CH
2OC (=O)-, be C
3Hydrocarbon carbonyl oxygen] and methoxycarbonyl [CH
3OC (=O)-, be C
2Hydrocarbon carbonyl oxygen].
" aromatic hydrocarbons oxygen carbonyl " refers to the ester substituting group, and wherein carbonyl carbon is the point with minute sub-connection, and this ester substituting group also comprises the alkylene group, and one of them tie point is connected with aromatic yl group.The example of aromatic hydrocarbons oxygen carbonyl group is C
6H
5CH
2O-C (=O)-, be C
8Aromatic hydrocarbons oxygen carbonyl group.
" alkyl " refers to the side chain or the unbranched-chain hydrocarbon fragment that contain the given number carbon atom and have a tie point.Example comprises that n-propyl (is C
3Alkyl), sec.-propyl (also is C
3Alkyl) and the tertiary butyl (be C
4Alkyl).Methyl symbol M e or CH
3Expression.
" alkylene " refers to biradical, and it is side chain or the unbranched-chain hydrocarbon fragment that contains the given number carbon atom and have two tie points.Example is propylidene [CH
2CH
2CH
2-, be C
3Alkylene].
" alkyl carboxyl " refers to side chain or unbranched, terminally is the hydrocarbon fragment of hydroxy-acid group [COOH].Example comprises carboxymethyl [HOOC-CH
2-, be C
2The alkyl carboxyl] and propyloic [HOOC-CH
2CH
2-, be C
3Alkyl carboxyl].
" aryl " refers to have the aromatic group of at least one ring, and described ring has the conjugated pi electron system, and comprises isocyclic aryl, heterocyclic aryl (being also referred to as heteroaryl groups) and diaryl group, and all these aromatic groups all can randomly be replaced.Usually preferred carbon ring aromatic yl group in compound of the present invention, wherein phenyl and naphthyl group are preferred carbon ring aromatic yl group.
" aryl " refers to the alkylene group, and one of them tie point is connected with aromatic yl group.The example of aryl group is benzyl group (Bn) [C
6H
5CH
2-, C
7Aryl group].
" alkyl alkylsulfonyl " refers to general formula-S (O)
2R
aGroup, wherein R
aBe hydrocarbyl group as herein defined.Alkyl alkylsulfonyl group is optionally by halogen or the optional aromatic yl group that replaces or other suitable substituting group replacement as well known to those skilled in the art.
" aryl sulfonyl " refers to general formula-S (O)
2R
bGroup, wherein R
bFor choosing as herein defined the aromatic yl group that replaces wantonly.The aryl sulfonic acid ester group comprises, but be not limited to the benzene sulfonate group, list of benzene sulfonate group, list-or many-replace-or many-halogeno-benzene sulfonate ester group, 2-bromo-benzene sulfonic acid ester group, 2,6-dichloro benzosulfonic acid ester group, penta fluoro benzene sulfonate ester group and 2,6-acid dimethyl ester group.The aryl sulfonyl group is optionally by halogen or alkyl or well known to a person skilled in the art that other suitable substituting group replaces.
" cyclic hydrocarbon radical " refers to can be saturated or unsaturated, and is the ring that is formed by carbon atom fully of monocycle, dicyclo or three rings.The example cyclopentenyl group (C of cyclic hydrocarbon radical group
5H
7-), it is (the C of five carbon
5) unsaturated cyclic hydrocarbon radical group.
" carbocyclic ring " refers to can be the ring of aryl rings or cyclic hydrocarbon basic ring, and the two all as hereinbefore defined.
" isocyclic aryl " refers to aromatic group, and the atom that wherein forms aromatic nucleus is carbon atom.Carbon ring aromatic yl group comprises monocycle carbon ring aromatic yl group such as phenyl, and two ring carbon ring aromatic yl group such as naphthyls, and all these isocyclic aryls all can randomly be replaced.
" halogen " or " halo " refer to-Cl ,-Br ,-F or-I.
" heteroatoms " refers to non-carbon atom, and wherein boron, nitrogen, oxygen, sulphur and phosphorus are preferred heteroatoms, and nitrogen, oxygen and sulphur are especially preferred heteroatoms in compound of the present invention.
" heteroaryl " refers to have 1 to 9 carbon atom, other atom is heteroatomic aryl, and comprises the 49th edition such as " Handbook of Chemistry and Physics (chemistry and physics handbook), ", 1968, R.C.Weast, editor; The Chemical Rubber Co., Cleveland, those heterocyclic systems described in the OH.Especially referring to Section C, Rules forNaming Organic Compounds, B.Fundamental Heterocyclic Systems (C part, nomenclature of organic compound principle, B, basic heterocyclic system).Suitable heteroaryl includes but not limited to furyl, thienyl, pyridyl, pyrryl, pyrimidyl, pyrazinyl, imidazolyl etc.
" hydroxy alkylene " refers to hydroxyl (OH) side chain of group or unbranched hydrocarbon fragment.Example comprises methylol (CH
2OH is C
1Hydroxy alkylene) and 1-hydroxyethyl (CHOHCH
3, be C
2Hydroxy alkylene).
" sulfo-alkyl " refers to the sulphur atom that replaced by hydrocarbyl group, for example sulphomethyl (CH
3S-is C
1The sulfo-alkyl).
" adjusting " means this ionic channel when relevant with the activity of ionic channel activity is in increase or reduction when giving the response of compound of the present invention or composition or method.Therefore, this ionic channel can be activated, and to transport more ion, perhaps can be blocked, so that this passage transports ion still less or do not transmit ion.
" the medicine acceptable carrier " that be used for the treatment of purposes is that pharmaceutical field is known, and for example is described in
Remingtons Pharmaceutical Sciences (Lei Mingdun pharmacopedics),Among the MackPublishing Co. (A.R.Gennaro edit.1985).For example, can use the salt solution of the phosphate buffered under Sterile Saline and the physiological pH.In pharmaceutical composition, can provide sanitas, stablizer, dyestuff or even seasonings.For example, can add Sodium Benzoate, Sorbic Acid and p-Hydroxybenzoate as sanitas.The same, 1449 pages.In addition, can use antioxidant and suspension agent, the same.
" the acceptable salt of medicine " refer to the acceptable organic or inorganic acid of the compounds of this invention and medicine (acid-adducting salt) or the acceptable organic or inorganic alkali of medicine (alkali adduct) in conjunction with and the salt of these compounds of forming, it has kept the biological effectiveness of the compounds of this invention and character and has been suitable at biology or other side.The acceptable salt example of medicine for example includes but not limited to " Handbook of Pharmaceutical Salts; Properties; Selection; and Use (drug salts handbook; character, choice and application) ", P.Heinrich Stahl and Camille G.Wermuth (Eds.), Published by VHCA (Switzerland) and Wiley-VCH (FRG), those salt described in 2002.The compounds of this invention can free alkali or the form of salt use, two kinds of forms all are contemplated within the scope of the present invention.
" the treatment significant quantity " of the compounds of this invention depends on route of administration, the type homoiothermous that is treated and considered physical trait concrete homoiothermous.These factors and with determine that this relationship between quantities is known for the practitioner of medical field.Can adjust this amount and medication, reaching best effect, but this depends on the other factors that factors such as body weight, recipe, the pharmacological agent carried out simultaneously and medical field technician know.
The composition of " containing the compounds of this invention " described herein is contained and is contained the composition that surpasses a kind of general formula compound of the present invention.
" inclusion compound " used herein refers to that fixed gases, liquid or compound are as inclusion complex, so that can process this title complex by solid form, and subsequently by the effect of solvent or by melting to discharge the material of the composition (or " object " molecule) that includes.Inclusion compound used among the present invention can be prepared by cyclodextrin.Known cyclodextrin has the ability with various molecule forming bag mixtures.For example, can be referring to Inclusion Compounds (inclusion compound), edited by J.L.Atwood, J.E.D.Davies, and D.D.MacNicol, London, Orlando, Academic Press, 1984; Goldberg, I., " The Significance of Molecular Type; Shape and Complementarity in Clathrate Inclusion (molecule type, shape and complementary importance in the inclusion inclusion) ", Topics in Current Chemistry (1988), Vol.149, pp.2-44; Weber, E.et al., " Functional Group Assisted ClathrateFormation-Scissor-Like and Roof-Shaped Host Molecules (the auxiliary inclusion compound formation-pushed together of functional group and roof-shaped host molecule) ", Topics in Current Chemistry (1988), Vol.149, pp.45-135; And MacNicol, D.D.et al., " Clathrates andMolecular Inclusion Phenomena (inclusion compound and molecule comprise phenomenon) ", ChemicalSociety Reviews (1978), Vol.7, No.1, pp.65-87.Knownly be transformed into stability and the solvability that cyclodextrin inclusion compound can increase some compound, therefore be conducive to it as the purposes of medicament.For example, can be referring to Saenger, W., " Cyclodextrin Inclusion Clathrates inResearch and Industry (the cyclodextrin encapsulated inclusion compound in research and the industry) ", Angew.Chem.Int.Ed.Engl. (1980), Vol.19, pp.344-362; United States Patent (USP) the 4th, 886, No. 788 (Schering AG); United States Patent (USP) the 6th, 355, No. 627 (Takasago); United States Patent (USP) the 6th, 288, No. 119 (Ono Pharmaceuticals); United States Patent (USP) the 6th, 110, No. 969 (OnoPharmaceuticals); United States Patent (USP) the 6th, 235, No. 780 (Ono Pharmaceuticals); United States Patent (USP) the 6th, 262, No. 293 (Ono Pharmaceuticals); United States Patent (USP) the 6th, 225, No. 347 (Ono Pharmaceuticals); And No. the 4th, 935,446, United States Patent (USP) (OnoPharmaceuticals).
" cyclodextrin " refers at least 6 cyclic oligosaccharides that the glucopyranose unit forms closing by by α (1-4) bond.The oligose ring forms anchor ring with the primary hydroxyl group of the glucosyl residue that is positioned at the narrow end of anchor ring.The secondary hydroxyl of glucopyranose is positioned at wide end.Known cyclodextrin can be in the aqueous solution forms inclusion complex by molecule being combined in its cavity with the hydrophobic molecule.The title complex that forms like this can protect " object " molecule not lose, be not subjected to oxygen, as seen reach the attack of UV-light and do not occur in the molecule and intermolecular reaction because of evaporation.Such title complex also is used for " fixing " volatile material, dissolves until this title complex runs into the environment of warm moist and is dissociated into guest molecule and cyclodextrin.For the purposes of the present invention, the cyclodextrin that will contain six glucose units is appointed as alpha-cylodextrin, and the cyclodextrin with 7 and 8 glucosyl residues is appointed as respectively beta-cyclodextrin and γ-cyclodextrin.Another the most frequently used selection of cyclodextrin name is with these compound called after ring-type amylose starchs.
Synthetic method/process described herein is especially with the general knowledge of this area, to enough guiding that provides of synthetic, the separation of the compounds of this invention and purifying.
Compound of the present invention
Such as United States Patent (USP) the 7th, 057, disclosed in detail in No. 053 and the disclosed patent application 99/50225 of PCT and 2004/099137, general formula (I) described in the summary of the invention above and that prepare by method disclosed herein and (II) compound can be used for treating irregular pulse, particularly auricular fibrillation.
Therefore, in an embodiment of the present invention, general formula (I) compound for preparing by method disclosed herein is following formula (Ia) compound, its single stereoisomers or its mixture or the acceptable salt of its medicine, ester, acid amides, title complex, inner complex, inclusion compound, solvate, polymorphic form, metabolite or prodrug:
This compound is general formula (I) compound, and wherein the hydroxyl substituent on the tetramethyleneimine basic ring is at 3, R
3, R
4And R
5At least one be hydrogen, and remaining R
3, R
4And R
5In one be methoxyl group on 3 of its benzyl rings that connects, and R
3, R
4And R
5In remaining be methoxyl group on 4 of its benzyl rings that connects, and it is named as (3R)-1-[(1R, 2R in this article)-2-[2-(3,4-Dimethoxyphenyl) oxyethyl group] cyclohexyl]-the 3-pyrrolidinol.
In another embodiment of the present invention, general formula (I) compound for preparing by method disclosed herein is to be selected from following compound, its single stereoisomers or its mixture or the acceptable salt of its medicine, ester, acid amides, title complex, inner complex, inclusion compound, solvate, polymorphic form, metabolite or prodrug:
In another embodiment of the present invention, general formula (I) compound for preparing by method disclosed herein is selected from:
(3R)-1-[(1R, 2R)-2-[2-(3,4-dimethoxy-phenyl) oxyethyl group] cyclohexyl]-3-pyrrolidinol mono-hydrochloric salts;
(3R)-1-[(1S, 2S)-2-[2-(3,4-dimethoxy-phenyl) oxyethyl group] cyclohexyl]-3-pyrrolidinol mono-hydrochloric salts;
(3S)-1-[(1R, 2R)-2-[2-(3,4-dimethoxy-phenyl) oxyethyl group] cyclohexyl]-3-pyrrolidinol mono-hydrochloric salts;
(3S)-1-[(1S, 2S)-2-[2-(3,4-dimethoxy-phenyl) oxyethyl group] cyclohexyl]-3-pyrrolidinol mono-hydrochloric salts;
(3R)-1-[(1R, 2R)-2-[2-(4-hydroxy 3-methoxybenzene base) oxyethyl group] cyclohexyl]-3-pyrrolidinol mono-hydrochloric salts;
(3R)-1-[(1R, 2R)-2-[2-(3-hydroxyl-4-p-methoxy-phenyl) oxyethyl group] cyclohexyl]-3-pyrrolidinol mono-hydrochloric salts;
(3R)-1-[(1R, 2R)-2-[2-(4-oxyethyl group-3-p-methoxy-phenyl) oxyethyl group] cyclohexyl]-3-pyrrolidinol mono-hydrochloric salts; And
(3R)-1-[(1R, 2R)-2-[2-(3-ethoxy-4-methoxyphenyl) oxyethyl group] cyclohexyl]-3-pyrrolidinol mono-hydrochloric salts.
In the above-mentioned embodiment, preferred embodiment is (3R)-1-[(1R, 2R)-2-[2-(3,4-dimethoxy-phenyl) oxyethyl group] cyclohexyl]-3-pyrrolidinol mono-hydrochloric salts, i.e. following formula: compound:
In another embodiment of the present invention, general formula (II) compound for preparing by method disclosed herein is following formula (IIa) compound, its single stereoisomers or its mixture or the acceptable salt of its medicine, ester, acid amides, title complex, inner complex, inclusion compound, solvate, polymorphic form, metabolite or prodrug:
This compound is general formula (II) compound, and wherein the hydroxyl substituent on the tetramethyleneimine basic ring is at 3, R
3, R
4And R
5At least one be hydrogen, and remaining R
3, R
4And R
5In one be methoxyl group on 3 of its benzyl rings that connects, and R
3, R
4And R
5In remaining be methoxyl group on 4 of its benzyl rings that connects, and it is named as (3R)-1-[(1S, 2R in this article)-2-[2-(3,4-Dimethoxyphenyl) oxyethyl group] cyclohexyl]-the 3-pyrrolidinol.
In another embodiment of the present invention, general formula (II) compound for preparing by method disclosed herein is to be selected from following compound, its single stereoisomers or its mixture or the acceptable salt of its medicine, ester, acid amides, title complex, inner complex, inclusion compound, solvate, polymorphic form, metabolite or prodrug:
In another embodiment of the present invention, general formula (II) compound for preparing by method disclosed herein is selected from:
(3R)-1-[(1S, 2R)-2-[2-(3,4-dimethoxy-phenyl) oxyethyl group] cyclohexyl]-3-pyrrolidinol mono-hydrochloric salts;
(3R)-1-[(1R, 2S)-2-[2-(3,4-dimethoxy-phenyl) oxyethyl group] cyclohexyl]-3-pyrrolidinol mono-hydrochloric salts;
(3S)-1-[(1R, 2S)-2-[2-(3,4-dimethoxy-phenyl) oxyethyl group] cyclohexyl]-3-pyrrolidinol mono-hydrochloric salts; And
(3S)-1-[(1S, 2R)-2-[2-(3,4-dimethoxy-phenyl) oxyethyl group] cyclohexyl]-3-pyrrolidinol mono-hydrochloric salts.
The present invention also provides can be by the protonated form of all compounds described in this specification sheets of method preparation of the present invention.That is, to each compound of describing in this specification sheets, the present invention also comprises the protonated quaternary amine form of compound that can be by method of the present invention preparation.The protonated quaternary amine form of these of described compound can solid phase form exist, for example exist with crystal or amorphous form, also can in solution, exist.The protonated quaternary amine form of these of described compound can be associated with the acceptable anionic counter ion of medicine, these gegenions include but not limited to that those are such as " Handbook of Pharmaceutical Salts; Properties; Selection; and Use (drug salts handbook; character, choice and application) ", P.Heinrich Stahl and Camille G.Wermuth (Eds.), Published by VHCA (Switzerland) and Wiley-VCH (FRG), those gegenions described in 2002.
In another embodiment of the present invention, use suitable chiral raw material, prepare general formula (II) compound by the similar method of preparation method with general formula described herein (I) compound.
The present invention also provides the intermediate by the novelty of method preparation disclosed herein.The intermediate for the preparation of general formula (I) compound by method preparation disclosed herein is to be selected from following compound, its single stereoisomers or its mixture or the acceptable salt of its medicine, ester, acid amides, title complex, inner complex, inclusion compound, solvate, polymorphic form, metabolite or prodrug:
With
Wherein:
Each R
3, R
4And R
5Be independently bromine, chlorine, fluorine, carboxyl, hydrogen, hydroxyl, methylol, sulfonyl methane amino, nitro, cyano group, sulfamyl, trifluoromethyl ,-CHF
2,-SO
2N (R
8) R
9,-OCF
3, C
2-C
7Alkylacyloxy, C
1-C
6Alkyl, C
1-C
6-oxyl, C
7-C
12Virtue-oxyl, C
2-C
7-oxyl carbonyl, C
1-C
6Sulfo-alkyl, aryl or-N (R
6) R
7Or
Each R
3, R
4And R
5Be hydrogen, hydroxyl or C independently
1-C
6-oxyl; But R
3, R
4And R
5Can not all be hydrogen simultaneously;
Each R
6, R
7, R
8And R
9All be independently selected from hydrogen, ethanoyl, methane sulfonyl or C
1-C
6Alkyl;
Each R
2aBe O or H
2, at least one R in each compound wherein
2aBe O;
Each R is H, C independently
2-C
5Acyl group or oxygen protecting group;
Each R ' is the optional alkyl alkylsulfonyl that replaces or the optional aryl sulfonyl that replaces; And
Each R
1Be the oxygen protecting group.
The intermediate for the preparation of general formula (II) compound by method preparation disclosed herein is to be selected from following compound, its single stereoisomers or its mixture or the acceptable salt of its medicine, ester, acid amides, title complex, inner complex, inclusion compound, solvate, polymorphic form, metabolite or prodrug:
Wherein:
Each R
3, R
4And R
5Be independently bromine, chlorine, fluorine, carboxyl, hydrogen, hydroxyl, methylol, sulfonyl methane amino, nitro, cyano group, sulfamyl, trifluoromethyl ,-CHF
2,-SO
2N (R
8) R
9,-OCF
3, C
2-C
7Alkylacyloxy, C
1-C
6Alkyl, C
1-C
6-oxyl, C
7-C
12Virtue-oxyl, C
2-C
7-oxyl carbonyl, C
1-C
6Sulfo-alkyl, aryl or-N (R
6) R
7Or
Each R
3, R
4And R
5Be hydrogen, hydroxyl or C independently
1-C
6-oxyl; But R
3, R
4And R
5Can not all be hydrogen simultaneously;
Each R
6, R
7, R
8And R
9All be independently selected from hydrogen, ethanoyl, methane sulfonyl or C
1-C
6Alkyl;
Each R
2aBe O or H
2, at least one R in each compound wherein
2aBe O;
Each R is H, C
2-C
5Acyl group or oxygen protecting group;
Each R ' is the optional alkyl alkylsulfonyl that replaces or the optional aryl sulfonyl that replaces; And
Each R
1Be the oxygen protecting group.
Method of the present invention
General formula (I) and general formula (II) compound contain with 1,2 arranges ether and the amido functional group that is positioned on the cyclohexane ring.Therefore, ether and amido functional group with respect to the other side and take the cyclohexane ring plane as trans relation or as cis relation, described plane of a loop is as with two-dimensional representation method represented paper.
The invention provides the synthetic method for the preparation of general formula as herein described (I) and general formula (II) compound.
Can prepare general formula (I) and general formula (II) compound by amino alcohol or alcohol by general method hereinafter described.Some general synthetic method of aminocyclohexyl ether has been described in WO99/50225 and the reference thereof.The disclosed patent application WO2004/099137 of PCT, the disclosed patent application WO2005/016242 of PCT and United States Patent (USP) the 7th, describe other in 057, No. 053 and other reference disclosed herein and can be used to prepare the method for general formula (I) and general formula (II) compound.
The method that be used for to split the diastereo-isomerism mixture of general formula (I) and general formula (II) intermediate that compound and this paper synthesized or racemic mixture be well known in the art (such as E.L.Eliel andS.H.Wilen, in Stereochemistry of Organic Compounds (stereochemistry of organic compound); John Wiley﹠amp; Sons:New York, 1994; Chapter7 and the reference of quoting thereof).The asymmetric conversion of for example crystallization of appropriate means (exist such as preferential crystallization method, additive under preferential crystallization method), racemic modification, chemical separation (as diastereomer for example non-mapping salt mixture formation with separate or the use of other resolution reagent; Separation by cooperation or inclusion compound), kinetic resolution (as by the tartrate titanium catalyst), enzyme fractionation (such as the lipase mediation) and chromatographic separation (as have chiral stationary phase and/or have HPLC or supercritical fluid chromatography and the correlation technique of simulated moving bed technology) are that adaptable some example is (referring to for example T.J.Ward, Analytical Chemistry, 2002,2863-2872).
The preparation of the acceptable salt of medicine, ester, acid amides, title complex, inner complex, inclusion compound, solvate, crystallization or amorphous form, metabolite, metabolic precursor thereof or the prodrug of the compounds of this invention is also contained in the present invention.By making hydroxyl or amido functional group can prepare the acceptable ester of medicine and acid amides with the acceptable as mentioned specified organic acid reaction of medicine respectively.Prodrug is by the medicine of chemically modified, and is that biology is inactive at its reactive site, but can or be modified into the biological active form of parent by one or more enzymes or the degraded of other physiological disposition.Usually, prodrug has different pharmacokinetic characteristics from female medical instrument, so that for example it easilier is absorbed by mucomembranous epithelial cell, it has the formation of better salt or solvability and/or its and has better whole body stability (such as the plasma half-life that increases).
Those skilled in the art will know that female medicine is carried out chemically modified to obtain prodrug, it comprises: (1) terminal ester or amide derivatives, and it is easily by esterase or lipase cracking; (2) terminal peptide, it can be by specificity or nonspecific protease identification; Or (3) select by film and the derivative that causes prodrug to gather in reaction site, and the combination of above-mentioned technology.The conventional steps that is used for selection and preparation prodrug derivant is described in H.Bundgaard, Design of Prodrugs (design of prodrug), (1985).Those skilled in the art are proficient in the preparation of prodrug and fully understand its meaning.
The acceptable title complex of medicine, inner complex, metabolite or the metabolic precursor thereof of the compounds of this invention also contained in the present invention.By retrieving various databases, the website of chemical abstracts and food and drug administration (FDA) for example, can access about the information of these term implications with and the reference of preparation.Can obtain from FDA such as following file: Guidance for Industry, " In Vivo Drug Metabolism/Drug Interaction Studies-Study Design; DataAnalysis; and Recommendations for Dosing and Labeling ", U.S.Department of Health and Human Services, Food and DrugAdministration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), November1999 (guidance for industry, " drug disposition metabolism/drug interaction research-research and design; data analysis and to the suggestion of dosage and mark ", U.S. Department of Health and Human Service, Food and Drug Administration, drug evaluation and research centre (CDER), biotechnological formulation is estimated and research centre (CBER), in November, 1999).Guidance for Industry, " In Vivo DrugMetabolism/Drug Interaction Studies in the DRUG DEVELOPMENTPROCESS:STUDIES IN VITRO ", U.S.Department of Health andHuman Services, Food and Drug Administration, Center for DrugEvaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), April1997 (guidance for industry, " drug disposition metabolism/drug interaction research; medicine opening method: in the in vitro study ", U.S. Department of Health and Human Service, Food and Drug Administration, drug evaluation and research centre (CDER), biotechnological formulation is estimated and research centre (CBER), in November, 1999).
Synthesis step described herein especially combines with this area general knowledge, provides enough guidance synthetic, separation and the purifying to carry out the compounds of this invention to those of ordinary skills.In addition, the personal feature of considering these embodiments and embodiment can be combined with the feature of one or more other embodiments or embodiment.
Those skilled in the art it is also understood that hereinafter in the described method, and the functional group of midbody compound may need by suitable protecting group protection.Such functional group comprises hydroxyl, amino, sulfydryl and carboxylic acid.The suitable protecting group of hydroxyl is comprised trialkyl silyl or two aryl silyls (such as t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethyl silyl), THP trtrahydropyranyl, benzyl etc.Suitable protecting group to amino, amidino groups and guanidine radicals comprises tert-butoxycarbonyl, benzyloxycarbonyl etc.Suitable protecting group to sulfydryl comprises-C (O)-R " (wherein R " be alkyl, aryl or aryl), to methoxy-benzyl, trityl etc.Suitable protecting group to carboxylic acid comprises alkyl, aryl or aryl ester.
Can or remove protecting group according to the standard technique interpolation, described standard technique is known to those skilled in the art, and as described herein.
Green, T.W.and P.G.M.Wuts, Protective Groups in OrganicSynthesis (protecting group in the organic synthesis) (1999), 3rd Ed. describes the application of protecting group in detail among the Wiley.
Can be under felicity condition well known by persons skilled in the art, by with inorganic or organic acid reaction and any or all compound described in any reaction scheme of this paper is converted into the acceptable salt of medicine.
In addition, any or all compound described in any reaction scheme of this paper can be placed the functional group to obtain expecting under the deprotection condition of standard.
In addition, any point at any synthetic schemes disclosed herein, raw material, intermediate or the product that forms thus can be split, take with independent enantiomer or diastereomeric separation raw material, intermediate or the product as the pure form of basic stereoisomerism.Then these independent enantiomers, diastereomer or its mixture can be used to the disclosed method of any reaction scheme of this paper, with the pure form of basic isomery of preparation general formula (I) compound, or its mixture.The method of resolution of racemates or other three-dimensional heterogeneous mixture be well known in the art (such as E.L.Eliel and S.H.Wilen, in Stereochemistry of Organic Compounds (stereochemistry of organic compound); John Wiley﹠amp; Sons:New York, 1994; Chapter7, and the reference of wherein quoting).Appropriate means can include but not limited to by the asymmetric conversion of Crystallization Separation steric isomer (such as preferential crystallization method, preferential crystallization method in the presence of additive), racemic modification or diastereo-isomerism mixture, chemical separation (as diastereomer for example non-mapping salt mixture formation with separate or the use of other resolution reagent; By cooperating or the separation of inclusion compound), kinetic resolution (as by the tartrate titanium catalyst), enzyme split (as the lipase mediation, carbonyl reductase mediates) and chromatographic separation (as have chiral stationary phase and/or have HPLC or supercritical fluid chromatography and the correlation technique of simulated moving bed technology) (referring to for example T.J.Ward, Analytical Chemistry, 2002,2863-2872).
In following reaction scheme and preparation, use following shortenings commonly used and abbreviation:
Et
2O (diethyl ether)
MTBE (methyl tertiary butyl ether)
TMSOTf (trimethyl silyl three fluoro sulfonates)
TMS-Cl (trimethylsilyl chloride)
P-TSA (tosic acid).
Following reaction scheme provides the de novo synthesis of pyrrolidinol ring in general formula (I) compound, and it has kept the trans relative configuration in the raw material.
The universal method that stereoselectivity prepares general formula (I) compound is as illustrated in the reaction scheme 1A, wherein R
1Be the oxygen protecting group, be preferably the optional benzyl that replaces; Select R
2With by process general formula (I) compound then cyclisation form general formula (3) compound, and R
2Be selected from but be not limited to following groups, wherein descend in the array structure
Line represents R in general formula (2) compound
2And between the OR group
Key:
Each R wherein
2aBe O or H
2(prerequisite is at least one R in each structure
2aBe O), and each Y is halogen; R is H, C
2-C
5Acyl group or oxygen protecting group; R
3, R
4And R
5Mutual-through type (I) compound defines in summary of the invention as mentioned; And the leavings group that the Q representative is good:
Reaction scheme 1A
Usually, be by at first in aprotic solvent such as toluene, methylene dichloride or ethyl acetate, using general formula (2) compound treatment general formula (1) compound, then using cyclization reagent such as C the synthetic of reaction scheme 1A formula of (I) compound
2-C
5Carboxylic acid halides or C
2-C
5Acid anhydrides approximately 0 ℃ to reflux temperature, process under the preferred reflux temperature, to form general formula (3) compound.Perhaps, at first in aprotic solvent with general formula (2) compound treatment general formula (1) compound to obtain corresponding intermediate, then this intermediate is processed to form general formula (3) compound with cyclization reagent.Then general formula (3) compound is placed under the standard deprotection condition well known by persons skilled in the art, in the presence of at catalyzer, carry out under suitable condition hydrogenation, to form general formula (4) compound.Then use general formula (5) compound treatment general formula (4) compound, reaction conditions is so that the stereochemistry spatial disposition of the oh group of general formula (4) compound is retained in resulting general formula (6) compound.Such condition includes but not limited in the aprotic solvent Lewis acid or Bronsted acid (HBF for example
4Et
2O, BF
3Et
2O, TMSOTf, ZnCl
2, TMS-Cl, CF
3SO
3H, HCl, CH
3SO
3H, H
2SO
4, p-TSA, camphorsulfonic acid, CF
3SO
3Ag), the existence of the Lewis acid of preferred catalytic amount or Bronsted acid.Before with general formula (4) compound treatment, optionally protect general formula (5) compound.The general formula that then will form like this (6) compound places under the standard restoration condition well known by persons skilled in the art to obtain general formula (I) compound.
Perhaps, it is illustrated that stereoselectivity prepares another universal method reaction scheme 1B described as follows of general formula (I) compound, wherein Q, R, R
2a, R
2, R
3, R
4And R
5In reaction scheme 1A, define as mentioned:
Reaction scheme 1B
Usually, the preparation of reaction scheme 1B formula of (I) compound is by at first use general formula (2) compound treatment general formula (1a) compound in aprotic solvent such as toluene, methylene dichloride or ethyl acetate, then the product of using general formula (5) compound treatment to obtain, reaction conditions are that the stereochemistry spatial disposition of 1 oh group is retained in the product that obtains when reacting with general formula (5) compound so that in general formula (1a) compound.Such condition includes but not limited in the aprotic solvent Lewis acid or Bronsted acid (HBF for example
4Et
2O, BF
3Et
2O, TMSOTf, ZnCl
2, TMS-Cl, CF
3SO
3H, HCl, CH
3SO
3H, H
2SO
4, p-TSA, camphorsulfonic acid, CF
3SO
3Ag), the existence of the Lewis acid of preferred catalytic amount or Bronsted acid.Then with the product cyclization reagent such as the C that obtain
2-C
5Carboxylic acid halides or C
2-C
5Acid anhydrides approximately 0 ℃ to reflux temperature, process to form general formula (6) compound under the preferred reflux temperature.The general formula that then will form like this (6) compound places under the standard restoration condition well known by persons skilled in the art to obtain general formula (I) compound.
For R
1With the oxygen protecting group of R can be such as T.W.Green and P.G.M.Wuts; Protective Groups in Organic Synthesis (protecting group in the organic synthesis); Wiley-Interscience; New York, any pure oxygen protecting group for the protection of alcohol described in the NY (1999) (" Green ").For R
1Preferred oxygen protecting group is the optional benzyl group that replaces, and wherein the optional substituting group on the benzyl group is as described in the Green.Be C for the preferred oxygen protecting group of R
2-C
5Carboxyl groups.General formula (1) compound, wherein R
1Be benzyl, can derive from BASF (Switzerland) (referring to the disclosed patent application WO96/23894 of PCT).General formula (1) compound can also derive from ASDI (601Interchange Blvd.Newark, DE19711, USA) and ABCR GmbH﹠amp; Co.KG (Im Schlehert10,76187Karlsruhe, Germany) or can prepare according to method known to those skilled in the art.
Can prepare general formula (5) compound by method known to those skilled in the art or method disclosed herein.In general formula (5) compound, the good leavings group of " Q " representative, it causes the formation of general formula (6) compound, so that trans relative configuration or the spatial disposition of the oh group on 1 carbon are retained in general formula (6) compound in general formula (4) compound or general formula (1a) compound, this causes the amine on the cyclohexyl ring and the substituent transconfiguration of ether or steric reservation in general formula (I) compound.Halo acetimide ester (such as 2,2,2-trifluoroacetyl imines ester or 2,2,2-tribromo-acetyl imines ester) is the preferred embodiment that contains general formula (5) compound of suitable Q group for the object of the invention.For the intermediate that forms among some general formula (4) compound among the reaction scheme 1A and/or the reaction scheme 1B; before carrying out with the esterif iotacation step of general formula (5) compound, may be necessary in general formula (5) compound, to introduce suitable protecting group.At for example T.W.Green and P.G.M.Wuts; Protective Groups in Organic Synthesis (protecting group in the organic synthesis); Wiley-Interscience; New York, NY (1999) reach and have provided suitable protecting group and corresponding deprotection condition in the reference of wherein quoting.
Other example of the suitable Q group of general formula (5) compound is provided in the following Table A.(forming summary of Application in the ether compound for the various examples of Q with alcohol, can be referring to for example Toshima K.and Tatsuta K.Chem.Rev.1993,93,1503; Tsuda T., Nakamura S.and Hashimoto S.Tetrahedron Lett.2003,44,6453; Martichonok V.and Whitesides G.M.J.Org.Chem., 1996,61,1702 reach the reference of wherein quoting).Shown in the following Table A, except halo acetimide ester (such as three halo acetimide esters, for example 2,2,2-trifluoroacetyl imines ester or 2,2,2-tribromo-acetyl imines ester) and outside other imines ester (such as penta fluoro benzene imines ester), other example for the synthesis of the suitable Q group of general formula (5) compound includes, but are not limited to O-carbonic ether and S-carbonic ether, comprises imidazoles carbonic ether and imidazoles thiocarbonic ester.The phosphoric acid ester example of Q group comprises diphenyl phosphoester, diphenylphosphine imines ester, phosphoramidate and O-sulfonyl group.
Select general formula (2) compound to obtain general formula (3) compound among the above-mentioned reaction scheme 1A and general formula (6) compound among the above-mentioned reaction scheme 1B.The example of general formula (2) compound includes, but are not limited to following compounds:
Wherein R is the oxygen protecting group; Each R
2aBe O or H
2, at least one R in each structure wherein
2aGroup is O, and Y is halogen.Can be according to for example Henrot, S.et al., SyntheticCommunications1986,16 (2), the operation described in the 183-190 is by oxysuccinic acid and C
2-C
5Acyl chlorides prepares general formula (2a) compound, perhaps can prepare general formula (2a) compound according to method known to those skilled in the art.General formula (2b) compound is commercially available, perhaps can prepare according to method known to those skilled in the art.Depend on protecting group, may need other protection and the deprotection steps product to obtain expecting.
Disclosed some step among above-mentioned reaction scheme 1A or the reaction scheme 1B can be merged, and not separate product or the desolventizing that wherein forms.This " one kettle way " synthetic specific examples is disclosed herein.
Above-mentioned reaction scheme 1A compares with preparation general formula (I) the compound method of report with reaction scheme 1B has following advantages:
1. each reactions steps can be easy to monitor by HPLC.
2. the total recovery of general formula (I) compound is higher than the total recovery of preparation general formula (I) compound method formula of (I) compound of report.
3. only need the acid of catalytic amount for esterif iotacation step, and do not need superstoichiometric amount (＞1 equivalent), although can use the acid of stoichiometry or hyperstoichiometry amount.
4. some step can be incorporated in the reaction vessel, and this can reduce the use for the treatment of time and factory.
Therefore 5. the method is effective enantioselectivity method, because do not produce undesired isomer, avoids expensive splitting step or avoids losing the expensive material that exists with undesired isomeric forms.
The more specifically method that stereoselectivity among the above-mentioned reaction scheme 1A prepares general formula (I) compound is illustrated among the following reaction scheme 1A1 for the preparation of general formula (I) compound, and wherein R is C
2-C
5Acyl group; Each R
2aBe O or H
2, at least one R in each structure wherein
2aBe O; R
3, R
4And R
5Definition such as mutual-through type (I) compound in above-mentioned the present invention's general introduction; AcCl represents C
2-C
5Acyl chlorides; R
1Represent the oxygen protecting group, the preferred optional benzyl that replaces, and Q represents leavings group:
Reaction scheme 1A1
Usually, at first with amine and the condensation in suitable solvent (such as toluene, methylene dichloride or ethyl acetate) of general formula (2a) compound of general formula (1), to obtain general formula (7) or general formula (8) compound.When showing the N-acidylate of general formula (1) compound, HPLC carries out when complete desolventizing under vacuum.According to Naylor, A.et al., 4-[(alkylamino) methyl] furo[3,2-c] pyridines:ANew Series of Selective κ-Receptor Agonists (4-[(alkylamino) methyl] furo [3,2-c] pyridine: a series of new selectivity κ-receptor agonist), J.Med.Chem. (1994), 37, similarly operation described in the 2138-2144, with the mixture of general formula (7)/(8) compound at C
2-C
5Carboxylic acid halides refluxes in the preferred Acetyl Chloride 98Min., so that cyclization to occur, obtains the succinimide of general formula (3).In the mixture of general formula (7)/(8) compound, add C
2-C
5Carboxylic acid halides, preferred Acetyl Chloride 98Min., and the method for first desolventizing does not show usefulness yet in cyclisation.
After removing excessive Acetyl Chloride 98Min., at ambient temperature general formula (3) compound is placed that (suitable solvent is such as the Pd/C-H in toluene, the methanol ethyl acetate under the standard hydrogenolysis condition
2, Ra-Ni-H
2, Pt/C-H
2) with except the deoxidation protecting group, obtain general formula (4) compound.General formula (4) compound with general formula (5) compound under the Lewis acid condition of catalysis (such as HBF
4Etherate) etherificate obtains the imines-ether of corresponding general formula (6).At last, with general formula (6) compound with suitable reductive agent, for example borane, NaBH
4/ Lewis acid, KBH
4, red aluminium is (referring to for example Alimardanov et al., Org.Proc.Res.﹠amp; Dev. (2004), 8,834-837) or lithium aluminum hydride (referring to for example above-cited Naylor, A.et al.) carry out follow-up reduction, obtain general formula (I) compound that exists with free alkali.Then in diethyl ether, use salt acid treatment general formula (I) compound, and in ethyl acetate, develop, obtain the hydrochloride of general formula (I) compound.
Perhaps, can not separate intermediate and/or not desolventizing (i.e. not conversion solvent) and carry out step in the above-mentioned reaction scheme, to form general formula (6) compound, then with its as indicated above processing, to form general formula (I) compound.In hereinafter the preparation part more detailed description preparation method's the example of this alternative general formula (I) compound.
The more specifically method that stereoselectivity among the above-mentioned reaction scheme 1A prepares general formula (I) compound is illustrated among the following reaction scheme 1A2 for the preparation of formula (Ia) compound, and formula (Ia) compound is general formula (I) compound, wherein R
1Represent the oxygen protecting group, be preferably the optional benzyl that replaces, and Ac represent ethanoyl:
Reaction scheme 1A2
In hereinafter the preparation part more detailed description concrete experiment condition and the parameter of above-mentioned reaction scheme 1A2.Should also be appreciated that, according to the disclosure, can with above-mentioned and similar method in preparation formula (Ia) compound and the acceptable salt of medicine thereof hereinafter, prepare following formula (Ib), formula (Ic), formula (Id), formula (Ie), formula (If), formula (Ig) and formula (Ih) compound and the acceptable salt of medicine thereof by using suitable raw material and reagent:
With
The more specifically method that stereoselectivity among the above-mentioned reaction scheme 1B prepares general formula (I) compound is illustrated among the following reaction scheme 1B1 for the preparation of general formula (I) compound, and wherein R is the oxygen protecting group; Ac is C
2-C
5Acyl group; Each R
2aBe O or H
2, at least one R in each structure wherein
2aBe O; R
3, R
4And R
5Define in the summary of the invention as mentioned, and Q represents leavings group:
Reaction scheme 1B1
By standard disassemble technique or can be from cis and trans-stereoisomer raw materials-trans Trans-4-Amino Cyclohexanol (formula (1a) compound) by method known to those skilled in the art.Usually; disclosed method is " one kettle way " acidylate, the ether coupling of acetimide ester and cyclization method among the reaction scheme 1B1; be that the method does not require separation of intermediates and/or desolventizing from reaction mixture; to obtain general formula (6) compound; then general formula (6) compound is placed under the reductive condition of standard, to form general formula (I) compound.More specifically, at ambient temperature, in suitable solvent such as toluene, methylene dichloride or ethyl acetate, use general formula (2a) compound of 1.05 equivalents to finish acidylate.Add general formula (5) compound, then preferred tribromo-acetyl imines ester adds the Lewis acid of catalytic amount, and preferred Tetrafluoroboric acid etherate obtains the mixture of various compositions, the material that wherein can want by HPLC identification.Then use C
2-C
5Carboxylic acid halides, preferred Acetyl Chloride 98Min. reaction mixture, and refluxed 1 hour, obtain the imines ether of general formula (6), can by the isolation technique of standard, such as flash column chromatography this imines ether be separated from reaction mixture.The follow-up reduction of general formula (6) compound and processing under the condition that forms the standard acid-adducting salt as with the diethyl ether solution processing of hydrochloric acid and develop, obtains the salt of general formula (I) compound, the preferably salt hydrochlorate in ethyl acetate.
Perhaps, can carry out reaction scheme 1B as shown in following reaction scheme 1B2, wherein R is C
2-C
5Acyl group; Each R
2aBe O or H
2, at least one R in each structure wherein
2aBe O; R
3, R
4And R
5Define in the summary of the invention as mentioned, and Q represents leavings group:
Reaction scheme 1B2
Briefly; the acidylate of raw material (1a) be by with this compound under suitable condensation condition; as at ambient temperature, in the methylene dichloride with the acid anhydride condensation of general formula (2a), obtain the mixture of general formula (9) and general formula (10) compound.Then use the mixture of general formula (5) these compounds of compound treatment, then add under suitable condition the Lewis acid of catalytic amount, preferred Tetrafluoroboric acid etherate obtains the mixture of general formula (11) and general formula (12) compound.Then under suitable cyclisation conditions, process the mixture of these compounds, for example process with cyclizing agent such as Acetyl Chloride 98Min., and refluxed 1 hour, to obtain general formula (6) compound, can pass through the standard isolation technique, such as flash column chromatography, general formula (6) compound be separated from reaction mixture.Mutual-through type under the standard restoration condition (6) compound carries out subsequent disposal and obtains general formula (I) compound, then general formula (I) compound is processed under the condition that forms the standard acid-adducting salt, for example process with the diethyl ether solution of hydrochloric acid, and in ethyl acetate, develop, obtain the salt of general formula (I) compound, the preferably salt hydrochlorate.
Also can stereoselectivity prepare general formula (I) compound by the other method of the present invention shown in the following reaction scheme 1C, wherein R is C
2-C
5Acyl group, R ' is the optional alkyl alkylsulfonyl that replaces or the optional aryl sulfonyl that replaces, X is halogen, R
3, R
4And R
5Define in the summary of the invention as mentioned:
Reaction scheme 1C
Raw material 2-chlorine pimelinketone (13) is commercially available from for example Aldrich Chemical Co.
Usually, 2-chlorine pimelinketone (13) under suitable condition by with 3 of general formula (5b), the reaction of the sodium alkoxide of 4-dimethoxy phenylethyl alcohol is easy to change into the ketone-ether of corresponding general formula (14).Use such as United States Patent (USP) the 6th, 617, in No. 475 disclosed method carry out asymmetric reduction or use chiral ruthenium catalyst under the Noyori reaction conditions (referring to for example Ohkmura, T.et al., J.Org.Chem. (1996), Vol.61, pp.4872) obtain general formula (15) compound.Then change general formula (15) compound into compound (16) under proper condition; so that-OR ' becomes active leavings group; for example use general formula R ' the X compound processes general formula (15) compound under alkaline condition; wherein R ' is the optional alkyl alkylsulfonyl that replaces or the optional aryl sulfonyl that replaces, and X is halogen.Leavings group in general formula (16) compound (O-R ') may be, but not limited to, and choose alkane sulfonic acid ester such as the trifluoromethayl sulfonic acid ester group (CF that replaces wantonly
3SO
3-) or methylsulfonic acid group (MsO-), optional aromatic yl sulphonate such as the benzene sulfonate group (PhSO that replaces
3-), single-or benzene sulfonate group of many-replacement, list-or many-halogeno-benzene sulfonate ester group, 2-bromo-benzene sulfonic acid ester group, 2,6-dichloro benzosulfonic acid ester group, penta fluoro benzene sulfonate ester group, 2,6-acid dimethyl ester group, toluenesulphonic acids ester group (TsO-) or m-nitrobenzene sulfonic acid ester (NsO-), or other good leavings group that is equal to.Also can change the oh group in general formula (15) compound into other suitable leavings group according to operation well known in the art.Leavings group can be any suitable leavings group when reacting with the nucleophilic reactant that three-dimensional chemical configuration is reversed known in the art, described nucleophilic reactant includes but not limited to M.B.Smith and J.March in " March ' s Advanced OrganicChemistry (March Advanced Organic Chemistry) ", Fifth edition, Chapter10, John Wiley﹠amp; Sons, Inc., New York, disclosed compound among the NY. (2001).With sodiumazide at nucleophilic substitution (S
N2) process general formula (16) compound under the condition, then obtain general formula (17) compound by in the presence of palladium catalyst, carrying out hydrogenation.Then in methylene dichloride, make the replacement maleic anhydride condensation of general formula (17) compound and general formula (2a2) obtain general formula (6b) compound, then general formula (6b) compound is placed under the standard restoration condition as herein described to obtain general formula (I) compound, then general formula (I) compound is processed under the condition that forms the standard acid-adducting salt, for example in the diethyl ether solution of hydrochloric acid, process and in ethyl acetate, develop, obtain the salt of general formula (I) compound, the preferably salt hydrochlorate.
Following reaction scheme provides the de novo synthesis of the pyrrolidinol ring in general formula (II) compound, and it keeps the cis relative configuration in the raw material.
Usually, use respectively following raw materials according:
Can be enough with described in above reaction scheme 1A and the reaction scheme 1B similarly mode prepare the above general formula described in the summary of the invention (II) compound.
Identical reagent and condition used in the reaction scheme of aforesaid preparation general formula (I) compound can be used to prepare general formula (II) compound from above-mentioned raw materials.For example, can be such as preparation general formula (II) compound as described in the following reaction scheme 2A, wherein cyclization reagent, general formula (2) compound and R, R
1, R
2, R
2a, R
3, R
4, R
5With Q as mentioned among the reaction scheme 1A define:
Reaction scheme 2A
Usually, can prepare the as mentioned general formula described in the reaction scheme 2A (II) compound with mode like the described preparation general formula of reaction scheme 1A above (I) compounds.
Perhaps, stereoselectivity prepares another universal method of general formula (II) compound and is illustrated in following reaction scheme 2B, wherein Q, R, R
2, R
2a, R
3, R
4And R
5Define among the reaction scheme 2A as mentioned:
Reaction scheme 2B
Usually, with reaction scheme 1B above in prepare that mode can prepare general formula (II) compound by reaction scheme 2B like general formula (I) compounds.
In reaction scheme 2A and reaction scheme 2B, the good leavings group of " Q " representative in general formula (5) compound, it causes the formation of general formula (21) compound, so that oh group cis relative configuration or the spatial disposition on 1 carbon is retained in general formula (21) compound in general formula (20) compound or general formula (22) compound, this causes amine and the substituent cis relative configuration of ether or steric reservation on the cyclohexyl ring in general formula (II) compound.
The more specifically method that stereoselectivity prepares the general formula described in the above-mentioned reaction scheme 2A (II) compound is illustrated among the following reaction scheme 2A1, wherein R, R
2a, R
3, R
4, R
5, AcCl, R
1With Q as mentioned reaction scheme 1A1 define:
Reaction scheme 2A1
Usually, with above-mentioned reaction scheme 1A1 in prepare mode like general formula (I) compounds, can prepare general formula (II) compound by disclosed method among the above-mentioned reaction scheme 2A1.
Perhaps, can not separate intermediate and/or not desolventizing (i.e. not conversion solvent) and carry out the step of above-mentioned reaction scheme, to form general formula (21) compound, then such as above-mentioned processing general formula (21) compound, to form general formula (II) compound.
The more specifically method that stereoselectivity prepares the general formula described in the above-mentioned reaction scheme 2A (II) compound is illustrated among the following reaction scheme 2A2 for the preparation of formula (IIa) compound, described formula (IIa) compound is general formula (II) compound, wherein R
1Represent the oxygen protecting group, the preferred optional benzyl that replaces, and Ac represents ethanoyl:
Reaction scheme 2A2
Usually, with above-mentioned reaction scheme 1A2 in prepare mode like general formula (I) compounds, can be in above-mentioned reaction scheme 2A2 preparation formula (IIa) compound.Should be appreciated that in the disclosure, by using suitable raw material and reagent, can prepare in mode similar to the above following formula (IIb), formula (IIc) and formula (IId) compound:
The more specifically method that stereoselectivity prepares the general formula described in the above-mentioned reaction scheme 2B (II) compound is illustrated among the following reaction scheme 2B1 for the preparation of general formula (II) compound, wherein R, Ac, R
2a, R
3, R
4, R
5With Q in the above-mentioned reaction scheme 1B1 definition:
Reaction scheme 2B1
Usually, with above prepare mode like general formula (I) compounds described in the reaction scheme 1B1, can prepare general formula (II) compound by disclosed method among the above-mentioned reaction scheme 2B1.
Perhaps, can as shown in following reaction scheme 2B2, carry out reaction scheme 2B, wherein R, R
2a, R
3, R
4, R
5With Q as mentioned among the reaction scheme 1B2 define:
Reaction scheme 2B2
Usually, with mode like preparation general formula (I) compounds described in the above-mentioned reaction scheme 1B2, can prepare general formula (II) compound by the method described in the above-mentioned reaction scheme 2B2.
Also can prepare general formula (II) compound by the other method of the present invention shown in the following reaction scheme 2C, wherein R is C
2-C
5Acyl group, R ' is the optional alkyl alkylsulfonyl that replaces or the optional aryl sulfonyl group that replaces, R
3, R
4And R
5Define in the summary of the invention as mentioned:
Reaction scheme 2C
Usually, with with preparation general formula (I) the compound similar fashion described in the above-mentioned reaction scheme 1C, can prepare general formula (II) compound by disclosed method among the above-mentioned reaction scheme 2C, difference is without asymmetric reduction step and hydrogenation afterwards to produce corresponding general formula (15) intermediate among the reaction scheme 1C, but the general formula among the above-mentioned reaction scheme 2C (14) compound can be processed under the standard restoration condition, for example use reductive agent, preferred NaBH
4Process, to produce general formula (31) compound, then general formula (31) compound is changed into active general formula (32) compound.Then with general formula (32) compound with reaction scheme 1C in general formula (16) compounds like mode process, to produce general formula (II) compound.
In illustrative mode, rather than with the restriction mode following preparation is provided.Except as otherwise noted, raw material and reagent can derive from known commercial supplier, such as Sigma-Aldrich fine chemicals (St.Louis, Missouri), and are standard class and purity; Perhaps can or carry out conversion from it by the described operation in this area and obtain, wherein by determining suitable operation by chemical abstracts or its index of American Chemical Society (Washington, DC) exploitation and publication.
Preparation 1
2-(R)-acetoxyl group-N-(2R-benzyloxy cyclohexyl] succsinic acid (7a) or 3-(R)-acetoxyl group-N-(2R-benzyloxy cyclohexyl) succsinic acid (8a)
To (1R, 2R)-2-benzyloxy cyclo-hexylamine (1) (BASF, WO 96/23894, CAS registration number 216394-06-8,0.80g, 3.90mmol) anhydrous methylene chloride (10mL) stirred solution small batch add 2R-acetoxyl group succinyl oxide (2a1) (781mg, 4.94mmol).To react the maintenance stirring at ambient temperature with under the inert atmosphere, be consumed until observe all raw materials by HPLC.When reaction is considered to carry out when complete, removing volatiles under vacuum obtains white solid (7a)/(8a) (1.45g, quantitative yield); MS (ES+) 364.2[M+H]
+, 386.2[M+Na]
+, 727.4[2M+H]
+, 749.4[2M+Na]
+MS (ES-) 362.1[M]
-, 725.3[2M]
- 1H-NMR (400MHz, CDCl
3) δ 1.12-1.41 (m, 4H), 1.58-1.61 (m, 1H), 1.73-1.76 (m, 1H), 2.02 (s, 3H, CH
3), 2.08-2.19 (m, 2H), 2.88 (d, 1H, J=5.6Hz), 3.19-3.28 (m, 1H), (3.72-3.81 m, 1H), 4.37-4.41 (m, 1H), (4.58-4.63 m, 1H), 5.34-5.38 (m, 1H), 6.29 (d, 1H, J=7.6Hz), 7.21-7.34 (m, 5H);
13C-NMR (100MHz, CDCl
3) δ 20.72,23.68,23.93,29.91,30.68,36.24,52.99,69.68,69.82,69.85,78.84,127.59,127.63,127.77,127.80,128.34,128.39,128.51,138.42,168.55,169.60,173.48.
Preparation 2
(3R)-and 1-((1R, 2R)-2-benzyloxy hexamethylene-1-yl)-2,5-dioxy pyrrolidin-3-yl acetic ester (3a)
2R-or 3R-acetoxyl group-N-(2R-benzyloxy cyclohexyl) succsinic acid (7a)/(8a) (1.40g, 3.85mmol) are dissolved in Acetyl Chloride 98Min. (15mL).The homogeneous solution that obtains was refluxed 45 minutes at 60 ℃.Removing volatiles under vacuum, and the resistates that obtains is further dry under high vacuum, obtain transparent faint yellow soup compound (3R)-1-((1R, 2R)-2-benzyloxy hexamethylene-1-yl)-2,5-dioxy pyrrolidin-3-yl acetic ester (3a); MS (ES+) 346.1[M+H]
+, 363.2[M+H
2O]
+, 368.1[M+Na]
+ 1H-NMR (400MHz, CDCl
3) δ 1.24-1.32 (m, 3H), 1.66-1.80 (m, 3H), (2.10 s, 3H), 2.12-2.29 (m, 2H), (2.40-2.45 m, 1H), 2.88-2.96 (m, 1H), (3.95-4.07 m, 1H), 4.23-4.27 (m, 1H), (4.57-4.61 m, 1H), 5.05 (br s, 1H), (7.18-7.20 m, 2H), 7.23-7.31 (m, 3H);
13C-NMR (100MHz, CDCl
3) δ 20.58,23.90,24.89,27.87,31.32,35.39,56.12,66.78,70.54,75.64,127.50,128.27,128.99,138.83,169.71,173.33,173.49.
Preparation 3
(3R)-and 1-((1R, 2R)-2-hydroxyl hexamethylene-1-yl)-2,5-dioxy pyrrolidin-3-yl acetic ester (4a)
To (1R, 2R)-benzyloxy cyclohexyl-2, add 10%Pd-C (110mg) in the MeOH solution of 5-dioxy-tetramethyleneimine-3-(R)-yl acetate (3a (1.1g, 3.18mmol)), and with reaction vessel H
2Wash twice.With reaction mixture at ambient temperature and H
2Lower (aerating ballon) stirs.After 4 hours, filter reaction mixture with the Celite pad.Filtrate is concentrated under vacuum, obtain white moisture absorption foam 1R, 2R-hydroxy-cyclohexyl-2,5-dioxy tetramethyleneimine-3-(R)-yl acetate (4a) (0.82g, yield 99%); MS (ES+) 256.1[M+H]
+, 278.0[M+Na]
+, 533.1[2M+Na]
+ 1H-NMR (400MHz, CDCl
3) δ 1.11-1.34 (m, 3H), 1.64-1.75 (m, 3H), 2.02-2.09 (m, 2H), 2.12 (s, 3H, CH
3), 2.22 (br s, 1H), 2.63 (dd, 1H, J=18.0Hz, 4.8Hz), 3.11 (dd, 1H, J=8.8Hz, J=18Hz), 3.82 (ddd, 1H, J=4.16Hz, J=10.6Hz, J=12.8Hz), 4.16 (ddd, 1H, J=4.4Hz, J=10.4Hz, J=14.8Hz), (5.34 dd, 1H, J=8.8Hz, J=4.8Hz);
13C-NMR (100MHz, CDCl
3) δ 20.52,24.16,24.98,27.77,35.03,35.40,58.44,67.43,68.40,170.11,173.89,174.08.
Preparation 4
3,4-(dimethoxy benzene oxyethyl group) tribromo-acetyl imines ester (5a)
3, the 4-dimethoxy phenylethyl alcohol (50mL) of packing in the reaction flask, and the mixture that obtains transferred to 12 ℃ (9-15 ℃).In reaction flask, add solid potassium hydroxide (5.0g, 1.62 equivalents) and methyltributylammonichloride chloride (75% weight ratio water's solution; 0.4g, 0.02 equivalent).Under maximum stirs, in reaction flask, slowly add Trichloroacetonitrile (10.0g, 1.26 equivalents) by feed hopper, keep temperature of reactor＜15 ℃.Reaction mixture was stirred 1-4 hour at 12 ℃ (9-15 ℃).Reaction mixture (20mL) is diluted with methyl tertiary butyl ether (MTBE), then be cooled to 3 ℃ (0-6 ℃).Then at 3 ℃ of (0-6 ℃) waters (3 * 20mL) washing MTBE layers.Under 40 ℃ of the highest bath temperature and decompression, MTBE solution is concentrated into driedly, and in remaining resistates, adds ethanol (55mL), mixture is stirred at 25 ℃ (22-28 ℃), until obtain clear solution.Ethanolic soln is cooled to 0 ℃ (3 to 3 ℃), to allow the product crystallization.Slurries water (77mL) is diluted, and mixture was descended stir about 1 hour at 0 ℃ (3 to 3 ℃).With dope filtration, and wash with cold (0-6 ℃) water (36mL).Wet cake is lower dry in vacuum and envrionment temperature (15-25 ℃), until moisture content (KF) is lower than 0.05%, obtain beige crystalline solid 3,4-(dimethoxy benzene oxyethyl group) tribromo-acetyl imines ester (5a) (yield 90-95%);
1H-NMR (300MHz, CDCl
3) δ 2.97 (t, 2H, J=7Hz, CH
2), 3.81﹠amp; 3.79 (2s, 6H, 2 * OCH
3), 4.42 (t, 2H, J=7Hz, CH
2O), 6.77-6.75 (m, 3H, Ar), 8.22 (br s, 1H, NH).
Preparation 5
1R, 2R-(3,4-dimethoxy benzene oxyethyl group) cyclohexyl }-2,5-dioxy-tetramethyleneimine-3R-yl acetate
(6a)
With 1R, 2R-hydroxy-cyclohexyl-2, toluene (8mL) solution of 5-dioxy tetramethyleneimine-3-(R)-yl acetate (4a) (0.75g, 3.08mmol) is cooled to 0 ℃.The Tetrafluoroboric acid diethyl ether title complex (0.2 equivalent, 87 μ L) of packing in the flask, and with mixture stir about 30 minutes at ambient temperature.Toluene (5mL) solution that in 15-20 minute, adds 3,4-(dimethoxy benzene oxyethyl group) tribromo-acetyl imines ester (5a) (1.05g, 1.05 equivalents) by syringe.Reaction mixture is stirred at ambient temperature, until reaction is finished.After reaction is finished, reaction mixture is cooled to-10 ℃, and the trichloroacetamide of filtering-depositing.With cold toluene (10mL) washing, and water (15mL) and salt solution (15mL) wash toluene filtrate according to this with filter cake.With dry (the anhydrous MgSO of organic layer
4), filter and concentrating under reduced pressure, to obtain the light brown soup compound.With crude product flash column chromatography purifying (silica gel; EtOAc: hexane, 1: 4v/v), and to obtain colourless thick soup compound 1R, 2R-(3,4-dimethoxy benzene oxyethyl group) cyclohexyl }-2,5-dioxy-tetramethyleneimine-3R-yl acetate (6a) (0.92g, yield 75%); MS (ES+) 420.2[M+H]
+, 437.2[M+H
2O]
+, 442.2[M+Na]
+ 1H-NMR (400MHz, CDCl
3) δ 1.10-1.33 (m, 3H), 1.61-1.75 (m, 3H), 1.91-2.02 (m, 1H), 2.07 (s, 3H), 2.17-2.20 (m, 1H), (2.34 dd, 1H, J=5.2Hz, J=18Hz), 2.59-2.76 (m, 3H), 3.13 (ddd, 1H, J=5.6Hz, J=8.8Hz, J=14.4Hz), 3.77-3.93 (m, 9H), 4.71 (br s, 1H), (6.46-6.67 m, 2H), 6.77-6.79 (m, 1H);
13C-NMR (100MHz, CDCl
3) δ 20.35,23.85,24.87,28.04,30.88,35.07,35.84,55.66,55.70,55.72,66.72,68.81,75.02,110.95,111.99,112.52,132.21,147.09,148.29,169.54,173.16,173.57.
Preparation 6
One kettle way prepares 1R, 2R-(3,4-dimethoxy benzene oxyethyl group) cyclohexyl }-2,5-dioxy-tetramethyleneimine-3R-yl acetate (6a) (acidylate, etherificate and cyclisation)
Under nitrogen, to the 1R of cold (0 ℃), add 2R-acetoxyl group succinyl oxide (2a1) (1.44g, 9.11mmol) in methylene dichloride (17.4mL) solution of 2R-Trans-4-Amino Cyclohexanol (1a) (1.00g, 8.68mmol).The permission reaction is warming up to envrionment temperature and stirred 1.5 hours.Disposable adding 3,4-(dimethoxy benzene oxyethyl group) tribromo-acetyl imines ester (5a) (3.41g, 10.4mmol) then is cooled to solution 0 ℃.Add HBF
4(359 μ L, Et
254% solution among the O 2.60mmol), and stirs the mixture that obtains 2.5 hours.Add Acetyl Chloride 98Min. (15mL) by syringe, and solution is warming up to backflow 1 hour, then before solvent removed in vacuo, allow to be cooled to envrionment temperature.Resistates is dissolved in ethyl acetate (25mL) and water (25mL), tells organic layer, and with ethyl acetate (2 * 25mL) aqueous layer extracted.The organic layer of water (25mL) and salt solution (25mL) washing merging is used MgSO according to this
4(anhydrous) drying is filtered and solvent removed in vacuo.The flash column chromatography of resistates on the silica gel (35% EtOAc/ hexane) obtains the yellow oil 1R of thickness, 2R-(3,4-dimethoxy benzene oxyethyl group) cyclohexyl }-2,5-dioxy-tetramethyleneimine-3R-yl acetate (6a) (680mg, yield 19%); MS (ES+) 420.1[M+H]
+, 437.1[M+H
2O]
+, 442.0[M+Na]
+
Preparation 7
Preparation (3R)-1-[(1R, 2R)-and 2-[2-(3,4-Dimethoxyphenyl) oxyethyl group] cyclohexyl]-3-pyrrolidinol (formula (Ia) compound)
At N
2Lower to 1R, 2R-(3,4-dimethoxy benzene oxyethyl group) cyclohexyl }-2,5-dioxy-tetramethyleneimine-3R-yl acetate (6a) (0.5g, 1.19mmol) anhydrous THF (2mL) solution in add borine-THF complex solution (1M, 8.0mL).Reaction mixture was stirred 18 hours at ambient temperature.Reaction mixture is cooled to 0 ℃, and makes the sluggish cancellation by the saturated MeOH solution (5.0mL) that adds HCl, and concentrated under vacuum, obtain faint yellow soup compound.With this soup compound at Et
2Development obtains beige solid (3R)-1-[(1R among the O (10mL), 2R)-2-[2-(3, the 4-Dimethoxyphenyl) oxyethyl group] cyclohexyl]-mono-hydrochloric salts (Ia) (340mg, yield 74%) of 3-pyrrolidinol, it has 79.5% HPLC purity;
1HNMR (400MHz, D
2O): δ 7.05-7.02 (m, 2H), 6.94 (dd, 1H, J2Hz, 8Hz), 4.43-4.38 (m, 1H), 4.11-4.04 (m, 1H), (3.89 s, 3H), 3.87 (s, 3H), 3.69 (overlapping dt, 1H, J 6Hz, 9Hz), 3.50-3.40 (m, 1H), (3.31-3.01 m, 5H), 2.97-2.79 (m, 2H), 2.37-2.30 (m, 1H), 2.10-1.70 (m, 5H), 1.45-1.12 (m, 4H).
Isomery purity: (3R)-1-[(1R, 2R)-2-[2-(3, the 4-Dimethoxyphenyl) oxyethyl group] cyclohexyl]-3-pyrrolidinol hydrochloride (Ia) is with respect to (3R)-1-[(1S, 2S)-and 2-[2-(3,4-Dimethoxyphenyl) oxyethyl group] cyclohexyl]-enantiomerism of 3-pyrrolidinol hydrochloride (Ib) is excessive to be 99.6%
Isomery purity: observe (3S)-1-[(1R, 2R of 4.02%)-and 2-[2-(3,4-Dimethoxyphenyl) oxyethyl group] cyclohexyl]-3-pyrrolidinol hydrochloride (Ic).
Preparation 8
Preparing as mentioned 1-prepares the similar mode described in 7 and prepares following general formula (I) compound:
(3R)-1-[(1S, 2S)-2-[2-(3,4-dimethoxy-phenyl) oxyethyl group] cyclohexyl]-3-pyrrolidinol (formula (Ib) compound),
1H NMR (D
2O, 400MHz) δ 7.06-7.01 (m, 2H), 6.94 (dd, 1H, J=8, J=2), 4.43 (br s, 1H), 4.06 (overlapping dt, 1H, J=9, J=6), 3.87,3.86 (two s, 2 * 3H), 3.75-3.67 (m, 1H), (3.52-2.80 m, 8H), 2.38-2.30 (m, 1H), (2.12-1.70 m, 5H), 1.47-1.10 (m, 4H);
(3S)-1-[(1R, 2R)-2-[2-(3,4-dimethoxy-phenyl) oxyethyl group] cyclohexyl]-3-pyrrolidinol (formula (Ic) compound),
1H NMR (D
2O, 400MHz) δ 6.88-6.82 (m, 2H), 6.78-6.73 (m, 1H), 4.29 (br s, 1H), 3.91-3.83 (m, 1H), 3.71,3.69 (two s, 2 * 3H), (3.58-3.47 m, 1H), 3.40-2.94 (m, 6H), (2.80-2.62 m, 2H), 2.22-2.10 (m, 1H), (2.03-1.55 m, 5H), 1.32-0.95 (m, 4H); And
(3S)-1-[(1S, 2S)-2-[2-(3,4-dimethoxy-phenyl) oxyethyl group] cyclohexyl]-3-pyrrolidinol (formula (Id) compound),
1H NMR (D
2O, 400MHz) δ 7.06-7.01 (m, 2H), 6.95 (dd, 1H, J=8, J=2), 4.40 (br s, 1H), 4.12-4.03 (m, 1H), 3.88,3.87 (two s, 2 * 3H), 3.73-3.66 (m, 1H), (3.50-2.80 m, 8H), 2.37-2.30 (m, 1H), (2.10-1.73 m, 5H), 1.45-1.10 (m, 4H).
Preparation 9
(1R, 2R)-1-{2-[2-(4-benzyloxy-3-methoxyl group-phenyl)-oxyethyl group]-cyclohexyl }-(3R)-2,5-dioxy-pyrrolidin-3-yl acetic ester
A. under 0 ℃ and nitrogen atmosphere to (3R)-1-((1R, 2R)-2-hydroxyl hexamethylene-1-yl)-2, add HBF in dry toluene (80mL) solution of 5-dioxy pyrrolidin-3-yl acetic ester (4a) (13.5g, 53.1mmol)
4OEt
2(3.40g, 21.2mmol, 2.90mL).Mixture was stirred 15 minutes, and in 30 minutes, add 2-(4-benzyloxy-3-p-methoxy-phenyl) ethyl-2,2, the dry toluene of 2-tribromo-acetyl imines ester (23.5g, 58.4mmol) (100mL) solution by feed hopper.Permission solution is warming up to envrionment temperature and stirred 3 hours.Then add entry (100mL) and stirred 15 minutes.Slowly add again 10%NaHCO
3The aqueous solution (10mL), and be stirred to and no longer observe bubble.Then mixture is transferred to separating funnel and with each layer separation.Use according to this 10%NaHCO
3The aqueous solution (3 * 150mL), water (150mL) and salt solution (100mL) washing organic phase.With organic phase Na
2SO
4Drying is filtered and is concentrated.Resistates is dissolved in toluene (200mL) and is cooled to-20 ℃, kept 18 hours, with precipitation trichloroacetamide by product.Mixture is filtered and filtrate is concentrated.
B. use (3R)-1-((1R, 2R)-2-hydroxyl hexamethylene-1-yl)-2,5-dioxy pyrrolidin-3-yl acetic ester (30.5g, 0.120mol) repeats aforesaid operations.The crude product of two reactions is merged, and by the column chromatography purifying (hexane-EtOAc, 4: 1, v/v).The chromatogram product is dissolved in toluene (200mL) and is cooled to-20 ℃, kept 48 hours, remaining trichloroacetamide by product is precipitated out.Mixture is filtered, and filtrate is concentrated, to obtain faint yellow oily thing (1R, 2R)-1-{2-[2-(4-benzyloxy-3-p-methoxy-phenyl) oxyethyl group] cyclohexyl }-(3R)-2,5-dioxy pyrrolidin-3-yl acetic ester (49.5g, the yield of merging are 58%); MS (ESI): 496.1[M+H]
+, 518.1[M+Na]
+
Preparation 10
(1R, 2R)-1-{2-[2-(4-benzyloxy-3-p-methoxy-phenyl) oxyethyl group] cyclohexyl }-(3R)-tetramethyleneimine-3-alcohol hydrochloride
Under nitrogen to (1R, 2R)-1-{2-[2-(4-benzyloxy-3-p-methoxy-phenyl) oxyethyl group]-cyclohexyl }-(3R)-2, slowly add BH in anhydrous THF (100mL) solution of 5-dioxy pyrrolidin-3-yl acetic ester (49.0g, 100mmol)
3THF (the THF solution of 1.0M, 400mmol, 400mL).Solution is heated to 80 ℃ and stirred 3 hours.Solution is cooled to envrionment temperature and slowly adds methyl alcohol (100mL) to no longer observing Bubble formation.With solution concentrated and add methyl alcohol HCl (methanol solution of 1.25M, 500mL).Solution is heated to 80 ℃ and stirred 1 hour.Then the solution of cooling is concentrated to obtain yellow soup compound (1R, 2R)-1-{2-[2-(4-benzyloxy-3-p-methoxy-phenyl) oxyethyl group] cyclohexyl }-(3R)-tetramethyleneimine-3-alcohol (50.8g, quantitative yield).Crude product is used for next step, and without being further purified;
1H NMR (400MHz, CDCl
3) δ 11.45 (br, s, 1H), 7.50-7.10 (m, 5H), (6.90-6.60 m, 3H), 4.22 (br, s, 1H), 4.00-3.85 (m, 5H), 3.75-3.55 (m, 2H), 3.35-2.50 (m, 7H), 2.45-2.20 (m, 2H), 2.08 (br, s, 1H), (1.90-1.50 m, 3H), 1.35-1.05 (m, 6H); MS (ESI): 426.2[M+H]
+
Preparation 11
(3R)-1-[(1R, 2R)-2-[2-(4-hydroxy 3-methoxybenzene base) oxyethyl group] cyclohexyl]-3-pyrrolidinol (formula (Ie) compound)
With compound (1R, 2R)-and 1-{2-[2-(4-benzyloxy-3-p-methoxy-phenyl) oxyethyl group] cyclohexyl }-(3R)-tetramethyleneimine-3-alcohol (50.3g, methyl alcohol 100mmol) (250mL) solution is transferred to the aqueous slurry form and Pd/C is housed in advance (10% weight ratio is in Parr shaker flask 4.0g).Place this bottle on the Parr hydrogenation reactor and find time.Then apply hydrogen pressure (60psi), and with container vibration 1 hour.Mixture is filtered with the Celite pad, and filtrate is concentrated.With resistates water-soluble (250mL), and use according to this ethyl acetate (3 * 200mL) and chloroform (10 * 150mL) washing.Use NaCl saturated the aqueous solution, and (4 * 200mL) wash with methylene dichloride.The organic extract liquid that merges is concentrated, and in resistates, add 5%NaHCO
3The aqueous solution (200mL).With suspension agitation 30 minutes, then use ethyl acetate (8 * 250mL) extractions.With the organic extract liquid anhydrous Na that merges
2SO
4Drying is filtered and is concentrated to obtain yellow powder.Then (3 * 50mL) develop with ethyl acetate with this powder, and apply high vacuum (oil pump), to obtain white powder (3R)-1-[(1R, 2R)-and 2-[2-(4-hydroxy-3-methoxy-phenyl) oxyethyl group] cyclohexyl]-3-pyrrolidinol (15.6g, yield 43%);
1H NMR (400MHz, CDCl
3) δ 6.82 (d, 1H, J=8.0), 6.75 (br s, 1H), 6.70 (d, 1H, J=8.0), (4.30-4.20 m, 1H), 3.87 (s, 3H), (3.78-3.70 m, 1H), 3.56 (q, 1H), (3.33 td, 1H, J=7.6, J=3.6), (2.97-2.89 m, 1H), 2.84-2.75 (m, 3H), (2.65 dd, 1H, J=10, J=5.2), (2.55-2.38 m, 2H), 2.09-1.95 (m, 2H), (1.91-1.82 m, 1H), 1.73-1.58 (m, 3H), 1.41-1.15 (m, 4H);
13C-NMR (100 MHz, CDCl
3) δ 23.25,23.68,27.59,29.21,34.42,36.70,48.84,56.06,59.93,63.68,69.83,71.29,79.59,111.98,114.60,121.65,131.35,144.23,146.67; IR:3436 (O-H stretching vibration), 1591,1515,1272,1098,1030,851cm
-1MS (ESI) 336.2 (M+1)
+
Preparation 12
(1R, 2R)-1-{2-[2-(3-benzyloxy-4-methoxyl group-phenyl) oxyethyl group] cyclohexyl }-2,5-dioxy-tetramethyleneimine-3-(R)-yl acetate
To (3R)-1-((1R, 2R)-and 2-hydroxyl hexamethylene-1-yl)-2, add Tetrafluoroboric acid diethyl ether title complex (3.2mL) in the anhydrous methylene chloride of 5-dioxy pyrrolidin-3-yl acetic ester (15.0g, 58.7mmol) (100mL) cooling (0 ℃) solution.The reaction mixture that obtains was stirred 20 minutes under 0 ℃, then in 30 minutes, add 2-(3-benzyloxy-4-methoxyl group-phenyl)-ethyl-2 by feed hopper, 2,2-tribromo-acetyl imines ester (24.8g, 61.6mmol, 1.05 equivalents) methylene dichloride (100mL) solution.Reaction mixture 0 ℃ of lower stirring, is reacted completely until analyze judgement by HPLC.With reaction mixture water (250mL) cancellation.Organic layer is separated from water layer, and use successively rare NaHCO
3(5% weight ratio solution, 2 * 100mL) and water (5 * 100mL) washing.With dry (the anhydrous MgSO of organic layer
4), filter and be evaporated to approximately 100mL solution.Solution is cooled to-20 ℃, kept 24 hours, and by removing by filter precipitation (trichloroacetamide).Filtrate further is concentrated into the approximately volume of 40mL.Repeat this process 3 times, until remove most of by product (trichloroacetamide).After filtering for the third time, with the filtrate vacuum concentration, to obtain faint yellow soup compound (1R, 2R)-1-{2-[2-(3-benzyloxy-4-methoxyl group-phenyl) oxyethyl group] cyclohexyl }-2,5-dioxy tetramethyleneimine-3-(R)-yl acetate (25g, yield 86%).
Preparation 13
(3R)-1-[(1R, 2R)-2-[2-(3-benzyloxy-4-p-methoxy-phenyl) oxyethyl group] cyclohexyl]-3-pyrrolidinol hydrochloride
At 0 ℃ and N
2Lower by feed hopper in 60 minutes to (1R, 2R)-and 1-{2-[2-(3-benzyloxy-4-methoxyl group-phenyl) oxyethyl group] cyclohexyl }-2,5-dioxy tetramethyleneimine-3-(R)-yl acetate (42.0g, 84.8mmol) anhydrous THF (300mL) solution in add borine-THF complex solution (1.0M, 297mL, 3.5 molar equivalents).Reaction mixture was heated straight gyrus stream 60 minutes.Reaction mixture is cooled to 0 ℃, and by adding slowly cancellation of methyl alcohol (approximately 15mL).The reaction mixture concentrating under reduced pressure removing THF, and is added methyl alcohol-HCl solution (approximately the methanol solution of 1.25M, 297mL, 3.5 equivalents) in the resistates.Then solution is heated to 70-80 ℃, kept 2 hours.Reaction mixture is cooled to envrionment temperature and concentrating under reduced pressure to obtain colourless soup compound (3R)-1-[(1R, 2R)-and 2-[2-(3-benzyloxy-4-methoxyl group-phenyl) oxyethyl group] cyclohexyl]-3-pyrrolidinol (35.0g, yield 89%).Sample is directly used in next step, and without being further purified.
Preparation 14
(3R)-1-[(1R, 2R)-2-[2-(3-hydroxyl-4-methoxyl group-phenyl) oxyethyl group] cyclohexyl]-3-pyrrolidinol (formula (If) compound)
To compound (3R)-1-[(1R, 2R)-2-[2-(3-benzyloxy-4-methoxyl group-phenyl) oxyethyl group] cyclohexyl]-the middle methyl alcohol (150mL) that adds of 3-pyrrolidinol (35.0g, 75.8mmol).This solution is transferred to the Parr reaction flask, and is keeping N
2Atmosphere is by add Pd/C (10% weight ratio on the activated carbon) in batches under the condition of reaction mixture.Then apply hydrogen pressure (60psi), and with reaction vessel vibration 3 hours, after this HPLC showed that raw material is fallen by completely consumed.Reaction mixture is filtered with the Celite pad, and filtrate is concentrated to obtain colourless soup compound (3R)-1-[(1R, 2R)-2-[2-(3-hydroxyl-4-methoxyl group-phenyl) oxyethyl group] cyclohexyl]-the 3-pyrrolidinol.Crude product is dissolved in the 1M HCl aqueous solution (450mL), and (8 * 250mL) wash with chloroform.Then water layer is saturated with solid NaCl (100g), and with (8 * 200mL) extractions of solution methylene dichloride.With dry (the anhydrous MgSO of the dichloromethane extraction liquid that merges
4), filtration and concentrating under reduced pressure are to obtain colourless soup compound (3R)-1-[(1R, 2R)-2-[2-(3-hydroxyl-4-methoxyl group-phenyl) oxyethyl group] cyclohexyl]-the 3-pyrrolidinol;
1H NMR (400MHz, D
2O) δ 7.01 (d, H, J=8.0), 6.86-6.83 (m, 2H), (4.42-4.36 m, 1H), 4.02 (overlapping dt, 1H, J=5.2, J=10.1), 3.85 (s, 3H), (3.67-3.55 m, 1H), 3.46-2.81 (m, 7H), (2.77-2.70 m, 1H), 2.34-2.27 (m, 1H), (2.11-1.74 m, 5H), 1.41-1.10 (m, 4H); IR:3439 (O-H stretching vibration), 1592,1510,1098,1022cm
-1MS (ESI) 336.1 (M+1)
+
Preparation 15
Prepare the similar fashion described in 14 to prepare as mentioned 9-, but use suitable alternative materials, prepare following general formula (I) compound:
(3R)-1-[(1R, 2R)-2-[2-(4-oxyethyl group-3-methoxyl group-phenyl) oxyethyl group] cyclohexyl]-3-pyrrolidinol (formula (Ig) compound); With
(3R)-1-[(1R, 2R)-2-[2-(3-oxyethyl group-4-methoxyl group-phenyl) oxyethyl group] cyclohexyl]-3-pyrrolidinol (formula (Ih) compound).
Preparation 16
(3R)-1-[(1R, 2R)-2-[2-(3,4-Dimethoxyphenyl) oxyethyl group] cyclohexyl]-3-pyrrolidinol (not conversion solvent preparation formula (Ia) compound)
A. to (1R, 2R)-2-benzyloxy cyclo-hexylamine (1) (125g, 0.609mol) toluene (1620g) stirred solution small batch add 2R-acetoxyl group succinyl oxide (2a1) (129g, 0.816mol, 1.34 equivalents) solid.Reaction mixture is stirred under 65 ℃ and inert atmosphere.Stir after 4 hours, do not observe raw material by HPLC.Reaction mixture is cooled to 48-50 ℃ and add Acetyl Chloride 98Min. (107g, 1.37mol, 2.24 equivalents).With mixture heating up to 60 ℃, obtain clear soln, and under a rear temperature, continue to stir 3 hours.Reaction mixture is cooled to envrionment temperature.After placing at ambient temperature 16 hours, the excessive Acetyl Chloride 98Min. of distillation under environmental stress.When arriving approximately 105 ℃ temperature, boiling point stops distillation.From reaction mixture, distill 172g (Acetyl Chloride 98Min. and toluene), with (the 3R)-1-((1R, 2R)-2-benzyloxy hexamethylene-1-yl)-2 that obtains 1714g, 5-dioxy pyrrolidin-3-yl acetic ester (3a) toluene solution.
B. at (3R)-1-((1R, 2R)-and 2-benzyloxy hexamethylene-1-yl)-2, add 10% Pd/C (6.3g in toluene (446g, the 0.151mol) solution of 5-dioxy pyrrolidin-3-yl acetic ester (3a), 50% wet weight ratio), and with reaction vessel H
2Wash twice.With reaction mixture at 18 ℃ and H
2(5bar) the lower stirring 8 hours, and at 45 ℃ and H
2(5bar) stirred 15.5 hours.Monitor reaction process with HPLC.Reaction mixture is filtered, filtrate is used toluene wash, and with the filtrate vacuum concentration, obtain white moisture absorption foam 3-(R)-1-[(1R, 2R)-and the 2-hydroxy-cyclohexyl]-2,5-dioxy pyrrolidin-3-yl acetic ester (4a) is (46.0g).
C. to 3-(R)-1-[(1R, 2R)-the 2-hydroxy-cyclohexyl]-2, add 12.5g Tetrafluoroboric acid diethyl ether in 5-dioxy pyrrolidin-3-yl acetic ester (4a) 800g toluene cooling (0 ℃) solution (120.6g).Add complete rear permission solution and be warming up to 20 ℃.Then add 3 of 171g, 4-(dimethoxy benzene oxyethyl group) tribromo-acetyl imines ester (5a) toluene (600g) solution (0.54mol) in during 1 hour.Reaction mixture is continued to stir 30 minutes, until undertaken fully by HPLC judgement reaction.After reacting completely, reaction mixture is cooled to-15 ℃, and the trichloroacetamide of filtering-depositing.Water (5 * 100g) wash filtrates.From organic layer distillation fraction solvent, to obtain dry 3-(R)-1-{ (1R, 2R)-2-[2-(3,4-Dimethoxyphenyl) oxyethyl group] cyclohexyl }-2, the organic product solution of 5-dioxy-pyrrolidin-3-yl acetic ester (6a).In this solution, add 10g toluene, obtain 471.5g solution, wherein contain 29.9% 3-(R)-1-{ (1R, 2R)-2-[2-(3, the 4-Dimethoxyphenyl) oxyethyl group] cyclohexyl }-2, the 5-dioxy-pyrrolidin-3-yl acetic ester (6a) is (141g).
D. at N
2Descend in 3.5 hours to 3-(R)-1-{ (1R, 2R)-2-[2-(3, the 4-Dimethoxyphenyl) oxyethyl group] cyclohexyl }-2, slowly add borine-THF complex solution (1M in cooling (0 ℃) solution of 5-dioxy-pyrrolidin-3-yl acetic ester (6a) in (29.9% toluene solution), 3.5 molar equivalent, 1016g).With reaction mixture reflux 1 hour.Reaction mixture is cooled to 0 ℃, and by adding methyl alcohol-HCl solution (the approximately 2.5M solution in the methyl alcohol, 373g) slowly cancellation.Then with vlil 2 hours (62-66 ℃), and the hydrolysis by HPLC monitoring borane complexes.Reaction mixture is cooled to envrionment temperature, and concentrating under reduced pressure is to obtain faint yellow soup compound (3R)-1-[(1R, 2R)-2-[2-(3,4-Dimethoxyphenyl) oxyethyl group] cyclohexyl]-3-pyrrolidinol (Ia).With crude product water-soluble (1192g), and with organic layer with methylene dichloride/chlorobenzene (1: 1; V/v) the mixture washing is 4 times.Then water layer is saturated with solid NaCl (316g), and with (2 * 930g) extractions of solution methylene dichloride.With dry (the anhydrous MgSO of the organic layer that merges
4, 223g, 8h), filtration and concentrating under reduced pressure are to obtain beige soup compound (3R)-1-[(1R, 2R)-and 2-[2-(3,4-Dimethoxyphenyl) oxyethyl group] cyclohexyl]-3-pyrrolidinol (Ia), its vacuum-drying after fixing is white foam shape thing.Product is dissolved in Virahol (279g) under refluxing, a distillation part (184.5g) is to obtain 170.5 g product solution.This solution to 2/3 (=add isopropyl acetate (250g) in 114g), then allow this solution to be cooled to 5 ℃, kept 4 hours, to form crystalline solid, with this solid filtering and dry 48 hours at ambient temperature, to obtain (3R)-1-[(1R, 2R of 6.5g)-2-[2-(3,4-Dimethoxyphenyl) oxyethyl group] cyclohexyl]-3-pyrrolidinol (Ia).
Although with reference to specific embodiment description and for example clear the present invention, it will be appreciated by those skilled in the art that and to carry out various adaptations, change, modification, to substitute, delete and add operation and scheme, and do not deviate from the spirit and scope of the present invention.Therefore, the present invention is intended to be defined by claims, and these claims should be tried one's best in rational scope for a person skilled in the art and explained widely.
Claims (37)
1. the preparation method of general formula (I) compound, its single stereoisomers or its mixture or the acceptable salt of its medicine:
Wherein:
R
3, R
4And R
5Be hydrogen, hydroxyl or C independently
1-C
6-oxyl; And
Described method comprises:
A) with general formula (4) compound:
Each R wherein
2aBe the hydrogen of O or two independent bondings, at least one R in wherein said general formula (4) compound
2aBe O, and R is H, C
2-C
5Acyl group or oxygen protecting group,
Under suitable reaction conditions, react with general formula (5) compound:
R wherein
3, R
4And R
5Be hydrogen, hydroxyl or C independently
1-C
6-oxyl, and Q is leavings group,
To form general formula (6) compound:
Each R wherein
2aBe the hydrogen of O or two independent bondings, wherein at least one R
2aBe O, R is H, C
2-C
5Acyl group or oxygen protecting group, and R
3, R
4And R
5Be hydrogen, hydroxyl or C independently
1-C
6-oxyl,
Described suitable reaction conditions is so that in a single day described general formula (4) compound reacts with described general formula (5) compound, and the trans relative configuration of oh group just is retained on 1 carbon of described general formula (6) compound on 1 carbon of described general formula (4) compound;
B) described general formula (6) compound is reduced to form general formula (I) compound under suitable condition; And
C) randomly, under proper condition, by with inorganic or organic acid reaction general formula (I) compound of preparation being converted into the acceptable salt of its medicine.
2. the method for claim 1, it also is included in the deprotection steps before general formula (4) compound and the reaction of general formula (5) compound, and wherein said deprotection steps comprises general formula (3) compound:
Each R wherein
2aBe the hydrogen of O or two independent bondings, wherein at least one R
2aBe O, R
1Be the oxygen protecting group, and R is H, C
2-C
5Acyl group or oxygen protecting group,
Under suitable deprotection condition, process to form above-mentioned general formula (4) compound.
3. method as claimed in claim 2, wherein R
1Be the optional benzyl group that replaces, and R is C
2-C
5Acyl group.
4. method as claimed in claim 2, it also comprises cyclisation step to form general formula (3) compound, and wherein said cyclisation step comprises the mixture reaction that makes under suitable condition general formula (7) compound or general formula (8) compound or general formula (7) compound and general formula (8) compound:
Each R wherein
1Be the oxygen protecting group independently, each R
2aBe the hydrogen of O or two independent bondings, and R is H, C
2-C
5Acyl group or oxygen protecting group,
To form above-mentioned general formula (3) compound.
5. method as claimed in claim 4, wherein R
1Be the optional benzyl that replaces, and R is C
2-C
5Acyl group.
6. method as claimed in claim 4, it also comprises condensation step to form the mixture of general formula (7) compound or general formula (8) compound or general formula (7) compound and general formula (8) compound, and wherein said condensation step comprises makes general formula (1) compound:
R wherein
1Be the oxygen protecting group,
With general formula (2a) compound:
Each R wherein
2aBe the hydrogen of O or two independent bondings, at least one R in wherein said general formula (2a) compound
2aBe O, R is H, C
2-C
5Acyl group or oxygen protecting group,
Under suitable condition reaction is to form the mixture of above-mentioned general formula (7) compound or general formula (8) compound or general formula (7) compound and general formula (8) compound.
7. method as claimed in claim 6, wherein R
1Be the optional benzyl group that replaces, and R is C
2-C
5Acyl group.
8. the method for claim 1, it also comprises the acid-adducting salt that forms general formula (I) compound.
9. such as the described method of arbitrary claim among the claim 1-8, wherein said general formula (I) compound is R
3, R
4And R
5Be hydrogen, hydroxyl or C independently
1-C
6-oxyl; But R
3, R
4And R
5Can not all be general formula (I) compound of hydrogen simultaneously.
10. method as claimed in claim 9, its formula of (I) compound is formula (Ia) compound or the acceptable salt of its medicine:
11. method as claimed in claim 9, its formula of (I) compound is selected from following compounds or the acceptable salt of its medicine:
And
12. the preparation method of general formula (I) compound, its single stereoisomers or its mixture or the acceptable salt of its medicine:
Wherein:
R
3, R
4And R
5Be hydrogen, hydroxyl or C independently
1-C
6-oxyl; And
Described method comprises:
A) with formula (1a) compound:
With general formula (2a) compound:
Under suitable condensation condition, react, to form product;
B) with a) described product and general formula (5) compound:
Wherein Q is leavings group, and R
3, R
4And R
5Be hydrogen, hydroxyl or C independently
1-C
6-oxyl,
Reaction is to form product under suitable coupling condition;
C) with b) described product under suitable cyclisation conditions, react, to form general formula (6) compound:
Each R wherein
2aBe the hydrogen of O or two independent bondings, wherein at least one R
2aBe O, R is H, C
2-C
5Acyl group or oxygen protecting group, and R
3, R
4And R
5Be hydrogen, hydroxyl or C independently
1-C
6-oxyl;
D) general formula (6) compound is reduced under suitable condition, to form above-mentioned general formula (I) compound; And
E) randomly, under proper condition, by with inorganic or organic acid reaction general formula (I) compound of preparation being converted into the acceptable salt of its medicine.
13. method as claimed in claim 12, wherein a) described product comprises the mixture of general formula (9) compound, general formula (10) compound or general formula (9) compound and general formula (10) compound:
Each R wherein
2aBe the hydrogen of O or two independent bondings, and R is H, C
2-C
5Acyl group or oxygen protecting group.
14. such as claim 12 or the described method of claim 13, wherein b) described product comprise the mixture of general formula (11) compound, general formula (12) compound or general formula (11) compound and general formula (12) compound:
Each R wherein
2aBe the hydrogen of O or two independent bondings, R is H, C
2-C
5Acyl group or oxygen protecting group, and R
3, R
4And R
5Be hydrogen, hydroxyl or C independently
1-C
6-oxyl.
15. such as claim 12 or the described method of claim 13, it also comprises the acid-adducting salt that forms general formula (I) compound.
16. such as claim 12 or the described method of claim 13, its formula of (I) compound is R
3, R
4And R
5Be hydrogen, hydroxyl or C independently
1-C
6-oxyl; But R
3, R
4And R
5Can not all be general formula (I) compound of hydrogen simultaneously.
17. method as claimed in claim 16, its formula of (I) compound are formula (Ia) compound or the acceptable salt of its medicine:
18. method as claimed in claim 16, its formula of (I) compound is selected from following compounds or the acceptable salt of its medicine:
And
19. be selected from following compound, its single stereoisomers or its mixture or the acceptable salt of its medicine:
Wherein:
Each R
3, R
4And R
5Be hydrogen, hydroxyl or C independently
1-C
6-oxyl;
Each R
2aBe the hydrogen of O or two independent bondings, wherein at least one R in each compound
2aBe O;
Each R is H or C independently
2-C
5Acyl group; And
Each R
1Be benzyl; But R
3, R
4And R
5Can not all be hydrogen simultaneously.
20. the preparation method of general formula (II) compound, its single stereoisomers or its mixture or the acceptable salt of its medicine:
Wherein:
R
3, R
4And R
5Be hydrogen, hydroxyl or C independently
1-C
6-oxyl; And
Described method comprises:
A) with general formula (20) compound:
Each R wherein
2aBe the hydrogen of O or two independent bondings, at least one R in wherein said general formula (20) compound
2aBe O, and R is H, C
2-C
5Acyl group or oxygen protecting group,
Under suitable reaction conditions, react with general formula (5) compound:
R wherein
3, R
4And R
5Be hydrogen, hydroxyl or C independently
1-C
6-oxyl, and Q is leavings group,
To form general formula (21) compound:
Each R wherein
2aBe the hydrogen of O or two independent bondings, wherein at least one R
2aBe O, R is H, C
2-C
5Acyl group or oxygen protecting group, and R
3, R
4And R
5Be hydrogen, hydroxyl or C independently
1-C
6-oxyl,
Described suitable reaction conditions is so that in a single day described general formula (20) compound and described general formula (5) compound react, and the trans relative configuration of oh group just is retained on 1 carbon of described general formula (21) compound on 1 carbon of described general formula (20) compound;
B) described general formula (21) compound is reduced to form general formula (II) compound under suitable condition; And
C) randomly, under proper condition, by with inorganic or organic acid reaction general formula (II) compound of preparation being converted into the acceptable salt of its medicine.
21. method as claimed in claim 20, it also is included in the deprotection steps before general formula (20) compound and the reaction of general formula (5) compound, and wherein said deprotection steps comprises general formula (19) compound:
Each R wherein
2aBe the hydrogen of O or two independent bondings, wherein at least one R
2aBe O, R
1Be the oxygen protecting group, and R is H, C
2-C
5Acyl group or oxygen protecting group,
Under suitable deprotection condition, process to form above-mentioned general formula (20) compound.
22. method as claimed in claim 21, wherein R
1Be the optional benzyl group that replaces, and R is C
2-C
5Acyl group.
23. method as claimed in claim 21, it also comprises cyclisation step to form general formula (19) compound, and wherein said cyclisation step comprises the mixture that makes general formula (23) compound or general formula (24) compound or general formula (23) compound and general formula (24) compound:
Each R wherein
1Be the oxygen protecting group independently, each R
2aBe the hydrogen of O or two independent bondings, and R is H, C
2-C
5Acyl group or oxygen protecting group,
React under suitable condition to form above-mentioned general formula (19) compound.
24. method as claimed in claim 23, wherein R
1Be the optional benzyl group that replaces, and R is C
2-C
5Acyl group.
25. method as claimed in claim 23, it also comprises condensation step to form the mixture of general formula (23) compound or general formula (24) compound or general formula (23) compound and general formula (24) compound, and wherein said condensation step comprises makes general formula (18) compound:
R wherein
1Be the oxygen protecting group,
With general formula (2a) compound:
Each R wherein
2aBe the hydrogen of O or two independent bondings, wherein at least one R
2aBe O, R is H, C
2-C
5Acyl group or oxygen protecting group,
Under suitable condition reaction is to form the mixture of above-mentioned general formula (23) compound or general formula (24) compound or general formula (23) compound and general formula (24) compound.
26. method as claimed in claim 25, wherein R
1Be the optional benzyl group that replaces, and R is C
2-C
5Acyl group.
27. method as claimed in claim 20, it also comprises the acid-adducting salt that forms general formula (II) compound.
28. such as the described method of arbitrary claim among the claim 20-27, its formula of (II) compound is R
3, R
4And R
5Be hydrogen, hydroxyl or C independently
1-C
6-oxyl; But R
3, R
4And R
5Can not all be general formula (II) compound of hydrogen simultaneously.
29. method as claimed in claim 28, its formula of (II) compound are formula (IIa) compound or the acceptable salt of its medicine:
30. method as claimed in claim 28, its formula of (II) compound is selected from following compounds or the acceptable salt of its medicine:
31. the preparation method of general formula (II) compound, its single stereoisomers or its mixture or the acceptable salt of its medicine:
Wherein:
R
3, R
4And R
5Be hydrogen, hydroxyl or C independently
1-C
6-oxyl; And
Described method comprises:
A) with formula (22) compound:
With general formula (2a) compound:
Under suitable condensation condition, react, to form product;
B) with a) described product and general formula (5) compound:
Wherein Q is leavings group, and R
3, R
4And R
5Be hydrogen, hydroxyl or C independently
1-C
6-oxyl,
Reaction is to form product under suitable ether coupling condition;
C) make b) described product under suitable cyclisation conditions, react, to form general formula (21) compound:
Each R wherein
2aBe the hydrogen of O or two independent bondings, R is H, C
2-C
5Acyl group or oxygen protecting group, and R
3, R
4And R
5Be hydrogen, hydroxyl or C independently
1-C
6-oxyl;
D) described general formula (21) compound is reduced under suitable condition, to form above-mentioned general formula (II) compound; And
E) randomly, under proper condition, by with inorganic or organic acid reaction general formula (II) compound of preparation being converted into the acceptable salt of its medicine.
32. method as claimed in claim 31, wherein a) described product comprises the mixture of general formula (25) compound, general formula (26) compound or general formula (25) compound and general formula (26) compound:
Each R wherein
2aBe the hydrogen of O or two independent bondings, and R is H, C
2-C
5Acyl group or oxygen protecting group.
33. such as claim 31 or 32 described method, wherein b) described product comprise the mixture of general formula (27) compound, general formula (28) compound or general formula (27) compound and general formula (28) compound:
Each R wherein
2aBe the hydrogen of O or two independent bondings, R is H, C
2-C
5Acyl group or oxygen protecting group, and R
3, R
4And R
5Be hydrogen, hydroxyl or C independently
1-C
6-oxyl.
34. such as claim 31 or 32 described methods, it also comprises the acid-adducting salt that forms general formula (II) compound.
35. such as claim 31 or 32 described methods, its formula of (II) compound is R
3, R
4And R
5Be hydrogen, hydroxyl or C independently
1-C
6-oxyl; But R
3, R
4And R
5Can not all be general formula (II) compound of hydrogen simultaneously.
36. method as claimed in claim 35, its formula of (II) compound are formula (IIa) compound or the acceptable salt of its medicine:
37. method as claimed in claim 35, wherein said general formula (II) compound is selected from following compounds or the acceptable salt of its medicine:
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US69098905P | 2005-06-15 | 2005-06-15 | |
| US60/690,989 | 2005-06-15 | ||
| US74824805P | 2005-12-07 | 2005-12-07 | |
| US60/748,248 | 2005-12-07 | ||
| PCT/US2006/023668 WO2006138673A2 (en) | 2005-06-15 | 2006-06-15 | Synthetic processes for the preparation of aminocyclohexyl ether compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101277931A CN101277931A (en) | 2008-10-01 |
| CN101277931B true CN101277931B (en) | 2013-04-24 |
Family
ID=39996521
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200680021196.6A Active CN101277931B (en) | 2005-06-15 | 2006-06-15 | Synthetic processes for the preparation of aminocyclohexyl ether compounds |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN101277931B (en) |
| ZA (1) | ZA200711207B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104610121B (en) * | 2015-01-07 | 2017-11-07 | 北京哈三联科技有限责任公司 | A kind of preparation method of Vernakalant hydrochloride |
| CN105294530B (en) * | 2015-11-30 | 2018-01-23 | 北京哈三联科技有限责任公司 | A kind of process for purification of Vernakalant hydrochloride |
| CN114031535B (en) * | 2021-11-30 | 2023-08-25 | 上海旭东海普药业有限公司 | Improved synthesis method of wiener kalant hydrochloride |
-
2006
- 2006-06-15 CN CN200680021196.6A patent/CN101277931B/en active Active
-
2007
- 2007-12-17 ZA ZA200711207A patent/ZA200711207B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CN101277931A (en) | 2008-10-01 |
| ZA200711207B (en) | 2009-08-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5159616B2 (en) | Synthetic process for the preparation of aminocyclohexyl ether compounds | |
| CN106470975B (en) | The synthesis of polycyclic carbamoylpyridone compound | |
| CN101208334B (en) | Novel cyclic amines | |
| CH651548A5 (en) | MERCAPTO-ACYL DERIVATIVES OF VARIOUS 4-SUBSTITUTED PROLINES WITH ANTI-HYPERTENSIVE ACTION. | |
| KR20240019063A (en) | Phenalkylamine and methods of making and using the same | |
| CN101277931B (en) | Synthetic processes for the preparation of aminocyclohexyl ether compounds | |
| CN103570600B (en) | A kind of chiral alpha methylene beta-lactam class compound and its preparation method and application | |
| CN101636404B (en) | (1r,6s)-2-azabicyclo[4.3.0] nonane-8,8-diphosphonic acid and its use in treating or preventing bone disorders, for example, osteoporosis or paget's disease | |
| TWI635076B (en) | Process for producing pyrrole derivative and intermediates for producing the same | |
| US8912345B2 (en) | Method for preparing optically pure (−)-clausenamide compound | |
| KR101677433B1 (en) | Ion exchanging process method for Tenofovir disoproxil fumarate in manufacturing synthesis and a preparation method of the Fast Dissolving Films for Oral Dosage of Tenofovir disoproxil fumarate | |
| WO2008103382A1 (en) | Method for assembling high-purity chemical libraries, compounds suppressing acetyl coenzyme a carboxylase activities discovered by same | |
| Luna-Freire et al. | An asymmetric substrate-controlled Morita–Baylis–Hillman reaction as approach for the synthesis of pyrrolizidinones and pyrrolizidines | |
| He et al. | RuPHOX-Ru catalyzed asymmetric Guerbet reaction of secondary alcohols with primary alcohols | |
| CN108239091A (en) | The fractionation of 1- cyclohexyl -2- (5H- imidazoles [5,1-a] iso-indoles) ethyl -1- ketone | |
| EP2238129B1 (en) | A method for the preparation of darifenacin hydrogen bromide | |
| CN110437230B (en) | Tertiary amine compound, diphosphine ligand, intermediate and preparation method thereof | |
| JP3780218B2 (en) | Novel chiral copper catalyst and method for producing N-acylated amino acid derivative using the same | |
| JP3738225B2 (en) | Novel chiral copper catalyst and method for producing N-acylated amino acid derivative using the same | |
| Naicker et al. | Optically active diaryl tetrahydroisoquinoline derivatives | |
| Schultz et al. | Asymmetric oxidations of enolates derived from Birch reduction of methyl 2-methoxybenzoate and (S)-2-methoxy-1-[[2'-(methoxymethyl) pyrrolidinyl] carbonyl] benzene | |
| CN102695698A (en) | Method for producing 3,4-disubstituted pyrrolidine derivative and production intermediate thereof | |
| CN107188786B (en) | Preparation method of optically pure cyclopentenol as medical intermediate | |
| CN115872820A (en) | Method for synthesizing chiral 2-functional group tetrahydroquinoline by biomimetic catalytic asymmetric hydrogenation | |
| KR20240057326A (en) | Manufacturing method of alkynyl amino acid ester derivative using photocatalytic reaction and use thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20190108 Address after: Geneva, Switzerland Patentee after: Colovio International Co.,Ltd. Address before: British Columbia Canada Patentee before: COLOVIO CANADA Co. Effective date of registration: 20190108 Address after: British Columbia Canada Patentee after: COLOVIO CANADA Co. Address before: British Columbia Canada Patentee before: Cardiome Pharma Corp. |
|
| TR01 | Transfer of patent right |