CN112778193A - Synthesis method of (S) -3- (4-chlorphenyl) -piperidine - Google Patents
Synthesis method of (S) -3- (4-chlorphenyl) -piperidine Download PDFInfo
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- CN112778193A CN112778193A CN202110305836.2A CN202110305836A CN112778193A CN 112778193 A CN112778193 A CN 112778193A CN 202110305836 A CN202110305836 A CN 202110305836A CN 112778193 A CN112778193 A CN 112778193A
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- piperidine
- chlorophenyl
- chlorphenyl
- chloro
- synthesis
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- GLXKIKPTKUQMAP-SNVBAGLBSA-N (3s)-3-(4-chlorophenyl)piperidine Chemical compound C1=CC(Cl)=CC=C1[C@H]1CNCCC1 GLXKIKPTKUQMAP-SNVBAGLBSA-N 0.000 title claims abstract description 19
- 238000001308 synthesis method Methods 0.000 title description 3
- 238000000034 method Methods 0.000 claims abstract description 13
- GLXKIKPTKUQMAP-UHFFFAOYSA-N 3-(4-chlorophenyl)piperidine Chemical compound C1=CC(Cl)=CC=C1C1CNCCC1 GLXKIKPTKUQMAP-UHFFFAOYSA-N 0.000 claims abstract description 11
- -1 5-chloro-2- (4-chlorophenyl) pentan-1-amine Chemical compound 0.000 claims abstract description 11
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 7
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 7
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 7
- 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 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 claims description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 4
- 239000012279 sodium borohydride Substances 0.000 claims description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 3
- MFESCIUQSIBMSM-UHFFFAOYSA-N I-BCP Chemical compound ClCCCBr MFESCIUQSIBMSM-UHFFFAOYSA-N 0.000 claims description 3
- GVPFVAHMJGGAJG-UHFFFAOYSA-L cobalt dichloride Chemical compound [Cl-].[Cl-].[Co+2] GVPFVAHMJGGAJG-UHFFFAOYSA-L 0.000 claims description 3
- 229960001270 d- tartaric acid Drugs 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- GJNGXPDXRVXSEH-UHFFFAOYSA-N 4-chlorobenzonitrile Chemical compound ClC1=CC=C(C#N)C=C1 GJNGXPDXRVXSEH-UHFFFAOYSA-N 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 6
- 239000003054 catalyst Substances 0.000 abstract description 5
- IVYMIRMKXZAHRV-UHFFFAOYSA-N 4-chlorophenylacetonitrile Chemical compound ClC1=CC=C(CC#N)C=C1 IVYMIRMKXZAHRV-UHFFFAOYSA-N 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 4
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 4
- 230000029936 alkylation Effects 0.000 abstract description 3
- 238000005804 alkylation reaction Methods 0.000 abstract description 3
- 230000008901 benefit Effects 0.000 abstract description 3
- 239000000047 product Substances 0.000 abstract description 3
- 230000003287 optical effect Effects 0.000 abstract description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 abstract 1
- 239000012467 final product Substances 0.000 abstract 1
- 238000011031 large-scale manufacturing process Methods 0.000 abstract 1
- 238000000746 purification Methods 0.000 abstract 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000002994 raw material Substances 0.000 description 5
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 3
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 3
- 229910003446 platinum oxide Inorganic materials 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- CAYQIZIAYYNFCS-UHFFFAOYSA-N (4-chlorophenyl)boronic acid Chemical compound OB(O)C1=CC=C(Cl)C=C1 CAYQIZIAYYNFCS-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- CBDGLHGPNJMCQK-UHFFFAOYSA-N 2-bromo-2-methylhexanoic acid Chemical compound CCCCC(C)(Br)C(O)=O CBDGLHGPNJMCQK-UHFFFAOYSA-N 0.000 description 1
- XDELKSRGBLWMBA-UHFFFAOYSA-N 3-iodopyridine Chemical compound IC1=CC=CN=C1 XDELKSRGBLWMBA-UHFFFAOYSA-N 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- INPLXZPZQSLHBR-UHFFFAOYSA-N cobalt(2+);sulfide Chemical compound [S-2].[Co+2] INPLXZPZQSLHBR-UHFFFAOYSA-N 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 150000004687 hexahydrates Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The invention relates to a method for synthesizing (S) -3- (4-chlorphenyl) -piperidine. Mainly solves the technical problems that optically pure (S) -3- (4-chlorphenyl) -piperidine is prepared by hydrogenating pyridine ring and then utilizing chiral SFC, the existing reaction conditions are harsh, the catalyst is expensive, the cost is high, and the like, and is not suitable for large-scale production. The synthesis of the invention comprises four steps, (1) alkylation of a site of 4-chlorobenzene acetonitrile; (2) reduction of 5-chloro-2- (4-chlorophenyl) penta-cyanide; (3) cyclizing 5-chloro-2- (4-chlorophenyl) pentan-1-amine to obtain (RS) -3- (4-chlorophenyl) -piperidine; (4) and (RS) -3- (4-chlorphenyl) -piperidine is subjected to chemical resolution to obtain a final product. The target product with the optical purity of more than 98 percent is obtained through four-step reaction. The method has the advantages of high yield, low cost, simple and convenient operation and purification, good economic benefit and more suitability for industrial production.
Description
Technical Field
The invention relates to a method for synthesizing (S) -3- (4-chlorphenyl) -piperidine. (S) -3- (4-chlorphenyl) -piperidine is an intermediate for synthesizing a medicament for treating neurological diseases, and belongs to the technical field of medicament synthesis chemical industry.
Background
The piperidine structural compound belongs to derivatives related to nitrogen-containing six-membered heterocyclic compounds, and has wide biological activity. The piperidine ring is a target of drug effect of a plurality of analgesic drugs, has wide scientific research and medicinal values, and particularly, chiral piperidine structural compounds become research hotspots of a plurality of scientific researchers.
Patent WO2015019103A1 discloses a synthesis method for synthesizing (S) -3- (4-chlorophenyl) -piperidine, which comprises the steps of using 3-iodopyridine as a raw material, carrying out Suzuki reaction on the raw material and 4-chlorobenzeneboronic acid, then carrying out catalytic hydrogenation on the raw material by platinum oxide to obtain racemic 3- (4-chlorophenyl) -piperidine, and finally separating the racemic 3- (4-chlorophenyl) -piperidine by using chiral SFC. The catalyst platinum oxide is very expensive, and chiral SFC is difficult to separate and amplify, so that the catalyst is high in cost and is not suitable for industrial production.
The synthesis route is as follows:
disclosure of Invention
The invention aims to disclose a method for synthesizing (S) -3- (4-chlorphenyl) -piperidine, which is simple, efficient, mild in condition and suitable for industrial production. Mainly solves the technical problems that the catalyst platinum oxide is very expensive, the chiral SFC is difficult to separate and amplify, the cost is very high, and the catalyst is not suitable for industrial production.
The technical scheme of the invention is as follows: a method for synthesizing (S) -3- (4-chlorphenyl) -piperidine is characterized by comprising the following steps: the method comprises the following steps:
step 1: adding 1-bromo-3-chloropropane into 4-chlorobenzonitrile in the presence of alkali, and reacting to obtain 5-chloro-2- (4-chlorophenyl) pentylcyanide;
step 2: reducing the 5-chloro-2- (4-chlorphenyl) pentylcyanide obtained in the step 1 in a methanol solution by using sodium borohydride and cobalt chloride to obtain 5-chloro-2- (4-chlorphenyl) pentylamine-1;
and step 3: cyclizing the 5-chloro-2- (4-chlorophenyl) pentan-1-amine obtained in the step 2 in the presence of potassium carbonate to obtain (RS) -3- (4-chlorophenyl) -piperidine;
and 4, step 4: resolving the (RS) -3- (4-chlorphenyl) -piperidine obtained in the step 3 with chiral acid to obtain (S) -3- (4-chlorphenyl) -piperidine;
the reaction formula is as follows:
in the reaction, the alkali in the first step is sodium hydrogen or potassium tert-butoxide, and preferably the alkali is sodium hydrogen; the chiral acid in the fourth step is D-camphorsulfonic acid or D-tartaric acid, and preferably the chiral acid is D-camphorsulfonic acid.
The invention has the beneficial effects that: the invention takes 4-chloro phenylacetonitrile as raw material to prepare the chiral (S) -3- (4-chlorphenyl) -piperidine with high optical purity through a-site alkylation, reduction of sodium borohydride with cobalt chloride, cyclization under alkaline condition and subsequent chemical resolution. The method has the advantages of cheap and easily-obtained raw materials, mild reaction conditions, simple method, high efficiency, high quality and yield, economy and effectiveness, and is suitable for industrial mass production.
Detailed Description
Example 1:
first step, alkylation of 4-chlorobenzeneacetonitrile at the a-position
A10L three-necked flask was charged with THF (6500 mL) as a solvent, and nitrogen gas was replaced. The mixture was cooled in an ice bath, and sodium hydrogen (60% by mass, 145.1 g, 3.6 mol) was added in portions. 4-Chlorobenzeneacetonitrile (500 g, 3.3 mol) was then added in portions, and after the addition was complete, stirring was carried out for 1 hour under ice bath. 3-chloro-1-bromopropane (524.7 g, 3.3 mol) was then added dropwise, and after the addition was complete, the mixture was stirred for 0.5 hour under ice bath. The reaction was quenched with water (3000 mL) while on ice. Extracted with ethyl acetate (2 × 3000 mL) and the organic phase dried over anhydrous magnesium sulfate. Filtering, and directly spin-drying the filtrate. The oil was purified by distillation under the reduced pressure to give 5-chloro-2- (4-chlorophenyl) penta-cyanohydrin (311 g, yield 41%).
Second step, reduction of 5-chloro-2- (4-chlorophenyl) penta-cyanol
2-bromo-2-methylhexanoic acid (300 g, 1.31 mmol), methanol (3500 mL), and hexahydrate of cobalt sulfide (375 g, 1.58 mol) were charged to a 10L three-necked flask, stirred, and cooled to-30 ℃. Sodium borohydride (149 g, 3.94 mol) was added in portions and reacted for 1 hour. 1000 mL of water was added, filtered, the filter cake extracted with ethyl acetate (1000 mL), and the filtrate was spin-dried directly. 5-chloro-2- (4-chlorophenyl) pentan-1-amine (241 g, 79% yield) was obtained.
The third step, cyclization of 5-chloro-2- (4-chlorophenyl) pentan-1-amine
To a 5L three-necked flask, 5-chloro-2- (4-chlorophenyl) pentan-1-aminic acid (240, 1.03 mol) and acetonitrile (2500 mL) were added. After stirring, potassium carbonate (69 g, 0.5 mol) was added and stirred at room temperature overnight. The next day, concentrate, add 2L of water, and extract with DCM (1L x 2). The organic phase was washed with brine, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was slurried with methyl tert-ether, filtered and dried to give the product (RS) -3- (4-chlorophenyl) -piperidine (108.3 g, 54% yield).
Fourthly, chemical Resolution of (RS) -3- (4-chlorophenyl) -piperidine
To a 5L three-necked flask were added (RS) -3- (4-chlorophenyl) -piperidine (103.1 g, 0.52 mol) and acetonitrile (2000 mL), and d-camphorsulfonic acid (69.7 g, 0.3 mol) was added. Heat to 50 ℃ and stir overnight. The next day, after cooling to 25 deg.C, the precipitated solid was collected by filtration, washed with 50mL of acetonitrile and dried to give camphorsulfonic acid salt of (S) -3- (4-chlorophenyl) -piperidine (93.6 g, 0.22 mol).
The solid was added to 350 mL of 0.5M aqueous sodium hydroxide and stirred overnight. The solid was collected by filtration the next day and washed with 100 mL of water to give the product (S) -3- (4-chlorophenyl) -piperidine (38.2 g, 74% yield) after drying.
1H NMR (DMSO-d 6): δ7.33 (d, J = 8.4 Hz, 2 H), 7.26 (d, J = 8.4 Hz, 2 H), 2.95-2.93 (m, 2H), 2.61-2.59 (m, 1H), 2.49-2.45 (m, 2H), 1.85-1.82 (m, 1H), 1.66-1.62 (m, 1H), 1.55-1.48 (m, 2H)。
Example 2, the base used in the first step was potassium tert-butoxide, the rest being the same as in example 1.
Example 3, the third step chiral acid was D-tartaric acid, the remainder of the example 1.
Claims (5)
1. A method for synthesizing (S) -3- (4-chlorphenyl) -piperidine is characterized by comprising the following steps: comprises the following steps:
step 1: adding 1-bromo-3-chloropropane into 4-chlorobenzonitrile in the presence of alkali, and reacting to obtain 5-chloro-2- (4-chlorophenyl) pentylcyanide;
step 2: reducing the 5-chloro-2- (4-chlorphenyl) pentylcyanide obtained in the step 1 in a methanol solution by using sodium borohydride and cobalt chloride to obtain 5-chloro-2- (4-chlorphenyl) pentylamine-1;
and step 3: cyclizing the 5-chloro-2- (4-chlorophenyl) pentan-1-amine obtained in the step 2 in the presence of potassium carbonate to obtain (RS) -3- (4-chlorophenyl) -piperidine;
and 4, step 4: the (RS) -3- (4-chlorophenyl) -piperidine obtained in step 3 is chemically resolved with a chiral acid and then dissociated with sodium hydroxide to obtain (S) -3- (4-chlorophenyl) -piperidine.
2. The process for the synthesis of (S) -3- (4-chlorophenyl) -piperidine according to claim 1, wherein: and in the first step, the alkali is potassium tert-butoxide or sodium hydrogen.
3. The process for the synthesis of (S) -3- (4-chlorophenyl) -piperidine according to claim 2, wherein: the alkali in the first step is sodium hydrogen.
4. The process for the synthesis of (S) -3- (4-chlorophenyl) -piperidine according to claim 1, wherein: and the chiral acid in the fourth step is D-camphorsulfonic acid or D-tartaric acid.
5. The process for the synthesis of (S) -3- (4-chlorophenyl) -piperidine according to claim 4, wherein: said chiral acid of said fourth step is d-camphorsulfonic acid.
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2021
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