CN102050801B - Method for preparing arylpiperazines derivative optical isomer - Google Patents
Method for preparing arylpiperazines derivative optical isomer Download PDFInfo
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- CN102050801B CN102050801B CN2009100758460A CN200910075846A CN102050801B CN 102050801 B CN102050801 B CN 102050801B CN 2009100758460 A CN2009100758460 A CN 2009100758460A CN 200910075846 A CN200910075846 A CN 200910075846A CN 102050801 B CN102050801 B CN 102050801B
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- optical isomer
- camsilate
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- 230000003287 optical effect Effects 0.000 title claims abstract description 72
- 238000000034 method Methods 0.000 title abstract description 33
- 150000001875 compounds Chemical class 0.000 claims abstract description 86
- 238000002360 preparation method Methods 0.000 claims abstract description 27
- 239000002904 solvent Substances 0.000 claims abstract description 15
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims abstract description 10
- MIOPJNTWMNEORI-XVKPBYJWSA-N (R)-camphorsulfonic acid Chemical compound C1C[C@]2(CS(O)(=O)=O)C(=O)C[C@H]1C2(C)C MIOPJNTWMNEORI-XVKPBYJWSA-N 0.000 claims abstract description 9
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims abstract description 8
- 239000000203 mixture Substances 0.000 claims abstract description 5
- 239000000935 antidepressant agent Substances 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- 229950005953 camsilate Drugs 0.000 claims description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 32
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 16
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- 238000012986 modification Methods 0.000 claims description 8
- 230000004048 modification Effects 0.000 claims description 8
- 238000001953 recrystallisation Methods 0.000 claims description 8
- 238000001556 precipitation Methods 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- -1 ether, dimethyl tertbutyl ether Chemical compound 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- SMZOGRDCAXLAAR-UHFFFAOYSA-N aluminium isopropoxide Chemical compound [Al+3].CC(C)[O-].CC(C)[O-].CC(C)[O-] SMZOGRDCAXLAAR-UHFFFAOYSA-N 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 230000002829 reductive effect Effects 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 3
- 238000005194 fractionation Methods 0.000 claims description 3
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 150000002825 nitriles Chemical class 0.000 claims description 2
- 150000003462 sulfoxides Chemical class 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 3
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical group COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims 1
- 150000003839 salts Chemical class 0.000 abstract description 6
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 abstract description 3
- 230000001430 anti-depressive effect Effects 0.000 abstract description 2
- 229940005513 antidepressants Drugs 0.000 abstract description 2
- 239000002244 precipitate Substances 0.000 abstract 2
- 230000003113 alkalizing effect Effects 0.000 abstract 1
- 239000003814 drug Substances 0.000 abstract 1
- 235000019441 ethanol Nutrition 0.000 description 12
- 229960004756 ethanol Drugs 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000008569 process Effects 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 238000004811 liquid chromatography Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical group O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910000000 metal hydroxide Inorganic materials 0.000 description 2
- 150000004692 metal hydroxides Chemical class 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229960001866 silicon dioxide Drugs 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- KGPGFQWBCSZGEL-ZDUSSCGKSA-N GSK690693 Chemical compound C=12N(CC)C(C=3C(=NON=3)N)=NC2=C(C#CC(C)(C)O)N=CC=1OC[C@H]1CCCNC1 KGPGFQWBCSZGEL-ZDUSSCGKSA-N 0.000 description 1
- LRQKBLKVPFOOQJ-YFKPBYRVSA-N L-norleucine Chemical compound CCCC[C@H]([NH3+])C([O-])=O LRQKBLKVPFOOQJ-YFKPBYRVSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 239000003174 triple reuptake inhibitor Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/092—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings with aromatic radicals attached to the chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
- C07D295/104—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/108—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Pain & Pain Management (AREA)
- Psychiatry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a method for preparing an arylpiperazines derivative, particularly optical isomer of N1-benzyl-N4-[1-(5'-chloro-6'-methoxy-2'-naphthoyl) amyl] piperazine (shown as a formula B). The method comprises the following steps of: dissolving an optical isomer mixture of the compounds of the formula B, particularly raceme and D-camphorsulfonic acid or L-camphorsulfonic acid in an appropriate solvent and reacting to form an S-type compound B, namely D-camphorsulfonate precipitate or an R-type compound B, namely L-camphorsulfonate precipitate, and alkalizing to obtain corresponding S or R-configured type compound B optical isomer. The invention also relates to the S or R-configured type compound B optical isomer, diastereomer salt prepared from the S or R-configured type compound B optical isomer and the D-camphorsulfonic acid or L-camphorsulfonic acid, and application of the S or R-configured type compound B optical isomer to preparation of the optical isomer of an antidepressant medicament of a formula A.
Description
Technical field
The present invention relates to especially N of a kind of aralkyl piperazine derivative
1-benzyl-N
4The preparation method of-[1-(5 '-chloro-6 '-methoxyl group-2 '-naphthoyl) amyl group] piperazine optical isomer.
Background technology
The applicant has disclosed 1-butyl-2-hydroxy aralkyl alcohol piperazine derivative N first in Chinese patent CN200810043821.8
1-benzyl-N
4-[1-butyl-2-(5 '-chloro-6 '-methoxyl group-2 '-naphthyl) hydroxyethyl] (structural formula is suc as formula shown in the A for piperazine, formula A compound hereinafter referred to as), it is a kind of 5-HT, NA, the triple reuptake inhibitors of DA selectivity, has stronger antidepressant activity.
In above-mentioned patent application, put down in writing and passed through N
1-benzyl-N
4-[1-(5 '-chloro-6 '-methoxyl group-2 '-naphthoyl) amyl group] piperazine (structural formula suc as formula shown in the B, hereinafter referred to as formula B compound) prepares the technological process of Soviet Union's formula or erythro form formula A compound raceme, shown in flow process 1:
Flow process 1
Owing to contain two chiral carbon atoms in the formula A compound structure, has (1S, 2S), (1R, 2R), (1S, 2R) and (1R, 2S) four optical isomers, therefore, expect its isomeric compound, still need the formula A compound raceme of Su Shi or erythro form is split, or adopt other method to prepare.
The applicant has adopted prochiral method to synthesize above-mentioned optical isomer in CN200810043821.8: take chirality nor-leucine 1 as raw material; amino is protected through phthaloyl; carboxyl is through the oxalyl chloride acidylate; generate compound 3; pass through Fu-Ke reacting generating compound 5 with compound 4 again; compound 5 obtains compound 7 through aluminum isopropylate reduction, hydrolysis, and compound 7 obtains compound 9 with compound 8 condensations, obtains optically pure target product (IX) through column chromatography for separation again.Concrete synthetic route is shown in flow process 2:
Flow process 2
The method raw material is easy to get, and products therefrom need not split, and optical purity is good.But also there is certain drawback in the method: 1) synthetic route is long; 2) severe reaction conditions needs waterless operation; 3) intermediate toxicity is large, has cytotoxicity such as intermediate 8; 4) total recovery is lower, no more than 1%; 5) product cost is high, and the per kilogram product cost reaches about 150,000 yuan.Therefore the method is difficult to realize suitability for industrialized production, brings difficulty for the further pharmaceutical research of formula A compound optical isomer.
Therefore, further study the novel method that finds a kind of suitability for industrialized to produce in the urgent need to the preparation method to formula A compound optical isomer.
Summary of the invention
In order to solve an above-mentioned prior art difficult problem, the present application people has carried out lot of experiments, as attempting the CN200810043821.8 synthesis technique is optimized, but all unsatisfactory.The contriver determines to attempt chemical resolution method, because formula A and formula B compound all are new compound, prior art does not have the method for splitting research of this respect, test like can only looking for a needle in a haystack by the contriver and grope, but fortunately, the contriver is take formula B compound raceme during as raw material, unexpectedly finds that adopting the chirality camphorsulfonic acid is resolution reagent, can obtain the formula B compound optical isomer of high-optical-purity.
Therefore, main purpose of the present invention be to provide a kind of optical isomer intermixture by split-type B compound especially racemic modification prepare the method for its optical siomerism.
Another object of the present invention is to provide the formula B compound of a kind of R or S configuration and the diastereoisomeric salt that the chirality camphorsulfonic acid forms.
Another purpose of the present invention is to provide the formula B compound of R or S configuration.
The inventive method is the optical isomer intermixture of formula B compound especially racemic modification and D-or L-camphorsulfonic acid to be dissolved in the suitable solvent react, make respectively to generate S-formula B compound-D-camsilate or R-formula B compound-L-camsilate precipitation, then obtain the formula B compound optical isomer of corresponding S or R configuration through alkalization.
Synthetic route is shown in flow process 3:
Flow process 3
Wherein:
The optical isomer intermixture of described D-or L-camphorsulfonic acid and formula B compound to be split especially racemic modification can any suitable ratio be used.Preferably, the optical isomer intermixture of D-or L-camphorsulfonic acid and formula B compound to be split the especially molar ratio of racemic modification is 10: 1～0.5: 1, more preferably 2: 1.
Described solvent has certain solubility to formula B compound, can dissolve fully in room temperature or heated condition following formula B compound.As known in the art, described solvent should have different to the solubleness of the diastereomer of formula B compound optical isomer and D-camphorsulfonic acid or the generation of L-camphorsulfonic acid.Described solvent can be selected from water, alcohol, ester, ketone, hydrochloric ether, ether, nitrile, acid amides, sulfoxide etc. or its arbitrary combination, but is not limited to this.Be preferably water, methyl alcohol, ethanol, Virahol, ethyl acetate, acetone, methylene dichloride, chloroform, ether, dimethyl tertbutyl ether, THF, acetonitrile, DMF, DMSO etc. or its arbitrary combination.
The racemic modification of the raw materials used formula B compound of the inventive method can be prepared with reference to the described method of CN200810043821.8.The CN200810043821.8 patent content is introduced the application as a reference.
The separation of the S-formula B compound that generates-D-camsilate or R-formula B compound-L-camsilate precipitation can be undertaken by method well known in the art, such as filter, centrifugal or decant etc., preferred method is for filtering.
If necessary, the S-formula B compound that obtains-D-camsilate or R-formula B compound-L-camsilate precipitation can be further purified by methods such as recrystallizations.Recrystallization solvent is selected from methyl alcohol, ethanol, Virahol, ethyl acetate, acetone, methylene dichloride, chloroform, ether, dimethyl tertbutyl ether, THF etc. or its arbitrary combination, but is not limited to this.
The S-formula B compound that obtains-D-camsilate or R-formula B compound-L-camsilate are removed the chiral acid resolution reagent through alkalization in water-insoluble organic solvents, obtain corresponding S-formula B compound or R-formula B compound optical isomer.Described alkali is selected from metal hydroxides, oxide compound, carbonate, supercarbonate and acid amides, is preferably metal hydroxides and carbonate, such as sodium hydroxide, yellow soda ash.
As known in the art, be used for wherein a kind of preparation method of optical isomer, after changing chiral selectors into its enantiomorph, can obtain another kind of optical isomer equally.
After isolating the S-formula B compound that generates-D-camsilate or R-formula B compound-L-camsilate precipitation, remaining filtrate or supernatant liquor obtain being rich in another kind of optical isomer through alkalization mixture, then available aforesaid method obtains another kind of optical isomer through further processing.
The diastereoisomeric salt that the formula B compound of the R that the inventive method obtains or S configuration and chiral selectors form is S-formula B compound-D-camsilate or R-formula B compound-L-camsilate.
The formula B compound optical isomer of the resulting R of the present invention or S configuration has following structural formula:
S-formula B compound
R-formula B compound
The S-formula B compound or the R-formula B compound optical isomer that obtain are reduced, obtain (1S, 2R), (1S, 2S) formula A compound optical isomer intermixture or (1R, 2R), (1R, 2S) then formula A compound optical isomer intermixture separates isomer mixture, obtains respectively (the 1S of formula A compound, 2R), (1S, 2S) optical isomer or (1R, 2R), (1R, 2S) optical isomer.
Described method of reducing can be to adopt NaBH
4Making reductive agent and reacting in methyl alcohol, also can be to adopt aluminum isopropylate to make reductive agent to react in Virahol, or other suitable method of reducing.
Described separation method can adopt 200: 1 methylene dichloride: methyl alcohol is that eluent carries out the silicagel column separation, also can adopt other proper method to separate.
The present invention passes through the formula B compound optical isomer especially successful fractionation of racemic modification; for the preparation of formula A compound optical isomer provides a variation route; for preparing in batches, its realization mass-producing opened up new route, also for it carries out further pharmaceutical research, develop provides favourable condition for new drug.
Embodiment
To help to understand the present invention by following embodiment, but not be construed as limiting the invention.In whole specification sheets, any and whole available reference disclosed, all by with reference to incorporating in the present patent application.Those of ordinary skills it is also understood that any change that does not deviate from spirit and scope of the invention that technical solution of the present invention is done, revise and are equal to replacement, all fall within the scope of the present invention.
Measure optical purity by chirality HPLC, condition is as follows: post-CHIRALPAK# bonding post, and flow velocity-1mL/min measures wavelength-236nm, and elutriant-normal hexane: Virahol: diethylamine=75: 25: 0.1, sample dissolution is in elutriant.
The peak figure situation of four optical isomers under above-mentioned chirality HPLC condition of the formula A compound that the method for utilizing the applicant to disclose first in Chinese patent CN200810043821.8 is synthetic is as shown in table 1:
Retention time (the t of four optical isomers of table 1 formula A compound
R)
| Compound structure type | (1S，2R) | (1R，2S) | (1R，2R) | (1S，2S) |
| t R(min) | 6.061 | 7.081 | 14.147 | 30.248 |
The preparation of embodiment 1S-formula B compound-D-camsilate
With R, S-formula B compound raceme (being prepared with reference to the described method of CN200810043821.8) 10g (0.0215mol) is added in the 300ml methyl alcohol, is heated to dissolving, adds D-camphorsulfonic acid 10g (0.0431mol), at 65 ℃ of reaction 3h.React complete, stir 2h at 20 ℃, crystallize out, suction filtration obtains S-formula B compound-D-camsilate 5.6g.Recording optical purity with Chiral liquid chromatography is 91.1%.
With the said products salt ethyl alcohol recrystallization, obtain optical purity greater than 99% S-formula B compound-D-camsilate 4.6g, mp=204.5-205.5 ℃, ultimate analysis measured value: C 65.05%, H7.01%, Cl 5.108%, N 4.06%, and O 13.92%, S 4.81% (calculated value: C
28H
33ClN
2O
2C
10H
16O
4S:C 65.43%, and H 7.08%, and Cl 5.08%, and N 4.02%, and O 13.77%, and S 4.62%).
The preparation of embodiment 2R-formula B compound-L-camsilate
With R, S-formula B compound raceme (being prepared with reference to the described method of CN200810043821.8) 20g (0.043mol) is added in the dehydrated alcohol of 500ml, be heated to dissolving, add L-camphorsulfonic acid 20g (0.0862mol), at 68 ℃ of reaction 2.5h.React complete, stir 2h at 10 ℃.Crystallize out, suction filtration obtains R-formula B compound-L-camsilate 12g.Recording optical purity with Chiral liquid chromatography is 91.0%.
With the said products salt acetone recrystallization, obtain optical purity greater than 99% R-formula B compound-L-camsilate 9g, mp=200.2-201.2 ℃, ultimate analysis measured value: C 65.02%, H 7.06%, and Cl 5.11%, N 4.00%, and O 13.98%, S 4.86% (calculated value: C
28H
33ClN
2O
2C
10H
16O
4S:C 65.43%, and H 7.08%, and Cl 5.08%, and N 4.02%, and O 13.77%, and S 4.62%).
Preparation S-formula B compound-D-camsilate under embodiment 3～11 different solvents conditions
With reference to embodiment 1 preparation method, preparation S-formula B compound-D-camsilate carries out recrystallizing and refining to it again under the differential responses solvent condition, and experimental result is as shown in table 2:
Table 2 embodiment 3～11 experimental results
| The embodiment numbering | Reaction solvent | Crude product weight (g) | Crude product optical purity (%) | Recrystallization solvent | Sterling weight (g) | Sterling optical purity (%) |
| 3 | 95% ethanol | 5.8 | 91.2 | Ethanol | 4.7 | 99.4 |
| 4 | Virahol | 5.2 | 90.6 | Ethyl acetate | 4.2 | 99.1 |
| 5 | Methyl alcohol-Virahol of 1: 1 | 5.5 | 91.0 | Virahol | 4.3 | 99.0 |
| 6 | Ethyl acetate | 5.2 | 90.6 | Acetone | 4.0 | 99.1 |
| 7 | Acetone | 4.9 | 90.2 | Methyl alcohol | 3.2 | 99.0 |
| 8 | Chloroform | 3.2 | 85.7 | Ether | 2.1 | 96.0 |
| 9 | The dimethyl tertbutyl ether | 3.6 | 89.2 | Methyl alcohol | 2.6 | 99.0 |
| 10 | Acetonitrile | 4.6 | 86.3 | Chloroform | 3 | 97.4 |
| 11 | Acetone-DMS0 of 3: 1 | 4.3 | 90.6 | Acetone | 3.2 | 99.0 |
Experimental result shows, under above-described embodiment experiment condition, all can obtain the diastereoisomeric salt of higher degree, consider from yield and product purity, reaction solvent is preferably methyl alcohol, ethanol, Virahol, aqueous alcohol solutions, ethyl acetate, acetone or its arbitrary combination, more preferably methyl alcohol, ethanol, methyl alcohol-Virahol of 1: 1, aqueous alcohol solutions; Recrystallization solvent is preferably methyl alcohol, ethanol, Virahol, ethyl acetate, acetone.
The preparation of embodiment 12S-formula B compound-D-camsilate and R-formula B compound-L-camsilate
Obtain S-formula B compound-D-camsilate 4.5g with reference to embodiment 1 preparation method, recording optical purity with chirality HPLC is 99.3%.
Mother liquor after filtering is processed with saturated sodium carbonate solution, obtain being rich in the formula B compound optical isomer intermixture of R isomer, refer again to embodiment 2 preparation methods and obtain R-formula B compound-L-camsilate 4.8g, recording optical purity with chirality HPLC is 99.1%.
The preparation of embodiment 13S-formula B compound
4.6g S-formula B compound-D-camsilate is added 100ml methylene dichloride and 100ml water, stir, transfer PH=9-10 with saturated sodium carbonate solution, phase-splitting, organic phase is steamed except organic solvent, obtains S-formula B compound 3g, and mp=80.6-81.4 ℃,
(c=1, CH
3Cl), measuring optical purity by chirality HPLC is 99.1%.
The preparation of embodiment 14R-formula B compound
Add in 200ml methylene dichloride and the 200ml water, stir, transfer PH=9-10 with the 2N sodium hydroxide solution, phase-splitting, organic phase is steamed except organic solvent, obtains R-formula B compound 5.8g,
(c=1, CH
3Cl), mp=82.2-82.8 ℃, measuring optical purity by chirality HPLC is 99.2%.
Embodiment 15 is by S-formula B compound preparation (1S, 2R) and (1S, 2S) formula A compound optical isomer
S-formula B compound isomers 4.65g (0.01mol) is dissolved in Virahol 70ml, adds aluminum isopropylate 7.14g (0.035mol), add anhydrous AlCl
30.46g (0.0035mol), 70 ℃ of reacting by heating 6h.Steaming desolventizes, and adds chloroform (100ml * 3), water (100ml) extraction, the combined chloroform layer, and dried over mgso is steamed except chloroform, obtains (1S, 2R) and (1S, 2S) formula A compound.
Said mixture is carried out silicagel column separate the eluent methylene dichloride: methyl alcohol=200: 1, what go out first post is (1S, 2S) isomer, t
R=30.24min, weight is 2g, yield 43%, recording optical purity with chirality HPLC is 99.5%.
After go out post for (1S, 2R) isomer, t
R=5.998min, weight is 1.8g, yield 39%, recording optical purity with chirality HPLC is 99.4%.
Embodiment 16 is by R-formula B compound preparation (1R, 2S) and (1R, 2R) formula A compound optical isomer
Method is with prepared (1S, 2S) and (1S, 2R) formula A compound optical isomer by S-formula B compound.Obtain (1R, 2S) isomer 1.9g, yield 41%, t
R=7.08min, recording optical purity with Chiral liquid chromatography is 99.2%; Obtain (1R, 2R) isomer 1.7g, yield 36%, t
R=14.15min, recording optical purity with Chiral liquid chromatography is 99.6%.
Claims (12)
1. the preparation method of the optical isomer of compound shown in the following structural formula B is characterized in that, adopts the chirality camphorsulfonic acid as resolution reagent, and the optical isomer intermixture of compound shown in the structural formula B is carried out chemistry fractionation.
B
2. the preparation method of the optical isomer of compound shown in the structural formula B as claimed in claim 1 is characterized in that, adopts the chirality camphorsulfonic acid as resolution reagent, and the racemic modification of compound shown in the structural formula B is carried out chemistry fractionation.
3. preparation method as claimed in claim 1, it is characterized in that: the optical isomer intermixture of formula B compound and D-or L-camphorsulfonic acid are dissolved in the suitable solvent react, make respectively to generate S-formula B compound-D-camsilate or R-formula B compound-L-camsilate precipitation, then obtain the formula B compound optical isomer of corresponding S or R configuration through alkalization.
4. preparation method as claimed in claim 2, it is characterized in that: the racemic modification of formula B compound and D-or L-camphorsulfonic acid are dissolved in the suitable solvent react, make respectively to generate S-formula B compound-D-camsilate or R-formula B compound-L-camsilate precipitation, then obtain the formula B compound optical isomer of corresponding S or R configuration through alkalization.
5. preparation method as claimed in claim 3 is characterized in that, described solvent is selected from water, alcohol, ester, ketone, hydrochloric ether, ether, nitrile, acid amides, sulfoxide or its arbitrary combination.
6. preparation method as claimed in claim 5, it is characterized in that described solvent is selected from water, methyl alcohol, ethanol, Virahol, ethyl acetate, acetone, methylene dichloride, chloroform, ether, dimethyl tertbutyl ether, THF, acetonitrile, DMF, DMSO or its arbitrary combination.
7. such as the described preparation method of any one among the claim 3-6, it is characterized in that, the S-formula B compound that generates-D-camsilate or R-formula B compound-L-camsilate precipitation are carried out recrystallization.
8. preparation method as claimed in claim 7, it is characterized in that the solvent that is used for recrystallization is selected from one or more mixture of methyl alcohol, ethanol, Virahol, ethyl acetate, acetone, methylene dichloride, chloroform, ether, methyl tertiary butyl ether and tetrahydrofuran (THF).
9.R-formula B compound-L-camsilate or S-formula B compound-D-camsilate.
10.R or the formula B compound optical isomer of S configuration, structural formula is as follows:
11.R or the formula B compound optical isomer of S configuration is preparing suc as formula the antidepressant drug N shown in the A
1-benzyl-N
4Purposes in-[1-butyl-2-(the 5 '-chloro-6 '-methoxyl group-2 '-naphthyl) hydroxyethyl] piperazine optical isomer.
A
12. the preparation method of formula A compound optical isomer, it is characterized in that, the formula B compound optical isomer aluminum isopropylate of R claimed in claim 10 or S configuration is reduced, with (the 1S that obtains, 2R), (1S, 2S) formula A compound optical isomer intermixture or (1R, 2R), (1R, 2S) formula A compound optical isomer intermixture separates, obtain respectively (1S, 2R), (1S, 2S) optical isomer or the (1R of formula A compound, 2R), (1R, 2S) optical isomer.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100758460A CN102050801B (en) | 2009-11-03 | 2009-11-03 | Method for preparing arylpiperazines derivative optical isomer |
| PCT/CN2010/001766 WO2011054185A1 (en) | 2009-11-03 | 2010-11-03 | Optical isomers of aralkyl piperazine derivative, preparation methods and uses thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100758460A CN102050801B (en) | 2009-11-03 | 2009-11-03 | Method for preparing arylpiperazines derivative optical isomer |
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| CN102050801B true CN102050801B (en) | 2013-05-29 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1381448A (en) * | 2002-05-08 | 2002-11-27 | 上海医药工业研究院 | Aralkylformylalkyl piperazine derivative and its application as brain nerve protector |
| CN1384102A (en) * | 2002-06-03 | 2002-12-11 | 上海医药工业研究院 | Alkyl alcohol piperazine derivative and its application in preparing medicine for treating depression |
| CN1948297A (en) * | 2005-10-10 | 2007-04-18 | 上海医药工业研究院 | Alkylol piperazine derivative optical isomer or its salt and its application |
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| CN101712658B (en) * | 2008-10-07 | 2012-03-14 | 石药集团中奇制药技术（石家庄）有限公司 | 1-butyl-2-hydroxy aralkyl piperazine derivative and application as antidepressant |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1381448A (en) * | 2002-05-08 | 2002-11-27 | 上海医药工业研究院 | Aralkylformylalkyl piperazine derivative and its application as brain nerve protector |
| CN1384102A (en) * | 2002-06-03 | 2002-12-11 | 上海医药工业研究院 | Alkyl alcohol piperazine derivative and its application in preparing medicine for treating depression |
| CN1948297A (en) * | 2005-10-10 | 2007-04-18 | 上海医药工业研究院 | Alkylol piperazine derivative optical isomer or its salt and its application |
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| CN102050801A (en) | 2011-05-11 |
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