CN101654445B - Compound for preparing ramelteon, preparation method thereof and application thereof - Google Patents
Compound for preparing ramelteon, preparation method thereof and application thereof Download PDFInfo
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- CN101654445B CN101654445B CN200810045870.5A CN200810045870A CN101654445B CN 101654445 B CN101654445 B CN 101654445B CN 200810045870 A CN200810045870 A CN 200810045870A CN 101654445 B CN101654445 B CN 101654445B
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- tetrahydrochysene
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- 0 *OC(C=C(CC1)[C@]2C1=CC=C1OCCC21)=O Chemical compound *OC(C=C(CC1)[C@]2C1=CC=C1OCCC21)=O 0.000 description 3
- STJFPPKIYLSEKU-UHFFFAOYSA-N OC(CC1c2c(CCO3)c3ccc2CC1)=O Chemical compound OC(CC1c2c(CCO3)c3ccc2CC1)=O STJFPPKIYLSEKU-UHFFFAOYSA-N 0.000 description 2
- YLXDSYKOBKBWJQ-LBPRGKRZSA-N CCC(NCC[C@H]1c2c(CCO3)c3ccc2CC1)=O Chemical compound CCC(NCC[C@H]1c2c(CCO3)c3ccc2CC1)=O YLXDSYKOBKBWJQ-LBPRGKRZSA-N 0.000 description 1
- FBBXLRYTHHBFHO-SCZZXKLOSA-N C[C@H]([C@H]1c2c(CCO3)c3ccc2CC1)C(O)=O Chemical compound C[C@H]([C@H]1c2c(CCO3)c3ccc2CC1)C(O)=O FBBXLRYTHHBFHO-SCZZXKLOSA-N 0.000 description 1
- TUFWVKLKUFXARX-YHYXMXQVSA-N N#C/C=C1\c2c(CCO3)c3ccc2CC1 Chemical compound N#C/C=C1\c2c(CCO3)c3ccc2CC1 TUFWVKLKUFXARX-YHYXMXQVSA-N 0.000 description 1
- WPIVLYZNFICYFP-UHFFFAOYSA-N N#CCC1c2c(CCO3)c3ccc2CC1 Chemical compound N#CCC1c2c(CCO3)c3ccc2CC1 WPIVLYZNFICYFP-UHFFFAOYSA-N 0.000 description 1
- ZZUIZMWFNOKNLN-UHFFFAOYSA-N O=C1c2c(CCO3)c3ccc2CC1 Chemical compound O=C1c2c(CCO3)c3ccc2CC1 ZZUIZMWFNOKNLN-UHFFFAOYSA-N 0.000 description 1
- STJFPPKIYLSEKU-VIFPVBQESA-N OC(C[C@H]1c2c(CCO3)c3ccc2CC1)=O Chemical compound OC(C[C@H]1c2c(CCO3)c3ccc2CC1)=O STJFPPKIYLSEKU-VIFPVBQESA-N 0.000 description 1
- WVDYBOADDMMFIY-UHFFFAOYSA-N SC1CCCC1 Chemical compound SC1CCCC1 WVDYBOADDMMFIY-UHFFFAOYSA-N 0.000 description 1
Classifications
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/582—Recycling of unreacted starting or intermediate materials
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention discloses 2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl) acetic acid(I) and an optical isomer(II) thereof; and the invention also discloses a method for preparing the compound and the application of the compound in the preparation of ramelteon which is a medicament for treating insomnia.
Description
Technical field
The invention belongs to pharmaceutical chemistry field, relate to 2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) acetic acid (I), optical isomer (II), its preparation method and at preparation insomnia medicine---the application in ramelteon (Ramelteon) medicine.
Background technology
Ramelteon chemistry is by name: (S)-N-[2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) ethyl] propionic acid amide, for a kind of melatonin receptor agonist of potent, highly selective, the melatonin MT on it and suprachiasmatic nucleus (also referred to as circadian clock)
1and MT
2acceptor has higher avidity, and not with MT
3receptor acting; Ramelteon is to MT
1and MT
2acceptor is the complete agonism of specificity, and to MT
1avidity, the selectivity of acceptor are strong compared with melatonin, and MT
1acceptor is considered to an integral part of sleep quality management, different from benzodiazepine medicine, and this product can not reduce human body rapid eye movement (REM) sleep.In addition, ramelteon is not combined with neurotransmitter receptors such as GABA receptor complexes, does not disturb the activity of most enzymes, therefore in certain scope yet, can avoid the dispersion attention (may result in an automobile accident, fall fracture etc.) relevant to GABA medicine, and drug habit and dependency.Ramelteon is mainly used in treating the type insomnia that has difficulty in going to sleep clinically, and chronic insomnia and short-term insomnia are also had to definite curative effect.Its chemical structural formula is as follows:
For synthesizing of optical activity ramelteon, at present existing bibliographical information many routes, these synthetic methods generally adopt the methods such as homogeneous phase asymmetric catalytic hydrogenation, the fractionation of preparative chiral column or enzymically hydrolyse fractionation to construct the palm of the hand center in molecule, now these pertinent literatures are listed below:
1.Sanjog?R，Chandrakant?ST，Mohanlal?PJ.et?al.WO2008062468
2.Shinichi?U，Eigo?M，Atsushi?I，Takashi?O，Shigeharu?S.WO2006030739
3.Toru?Y，Masayuki?Y，Mari?A.et?al.Tetrahedron：Asymmetry2006，17(2)：184-190
4.Osamu?U，Kohji?F，Ryosuke?T.et?al.J?Med?Chem2002，45(19)：4222-4239
5.Shigenori?O，Masaomi?M.WO9963977
6.Takashi?I，Takashi?M，Hidenori?U.et?al.JP11140073
7.Tom?Y，Mari?A，Mitsuru?K.JP11080106
8.Shigenori?O，Osamu?U，Kohji?F.et?al.WO9732871
The method of above-mentioned synthesis of optically active ramelteon, exist to be used cost of material higher and be not easy to obtain (as: [RuCl (benzene) (R)-BINAP] Cl, Ru (OAc)
2-[(R)-BINAP], Ru
2cl
4[(R)-BINAP]
2nEt
3, hydroamidase etc.); Severe reaction conditions (needing absolute anhydrous solvent, high-pressure hydrogenation); Reactions steps is many, total recovery is on the low side; In preparation process, " three wastes " discharge is serious; Operation and last handling process are loaded down with trivial details, the deficiency such as heavy metals exceeding standard in product, make the preparation cost of ramelteon higher, and a large amount of preparations are restricted.Therefore, this area still need to develop that raw material is cheap and easy to get, reaction conditions is gentle, easy and simple to handle, chemical yield and optical purity is high, the ramelteon synthetic method of " environmental protection ".
Summary of the invention
The object of the invention is to disclose a kind of novel key intermediate for the preparation of ramelteon (Ramelteon)---2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) acetic acid (I) and its optical isomer (II);
Another object of the present invention is to disclose the preparation method of such novel cpd;
The 3rd object of the present invention is to disclose such key intermediate at preparation insomnia medicine---the application in ramelteon medicine.
The chemical structural formula of 2-provided by the present invention (1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) acetic acid (I) and its optical isomer (II) is:
In formula: the chiral centre of compound (II) can be S-or R-configuration.
Key intermediate for the preparation of ramelteon (Ramelteon) proposed by the invention---2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) acetic acid (I) and its optical isomer (II) can prepare by the following method:
Wherein, R is the Saturated alkane of H, 1～10 carbon, the aromatic base of 6～10 carbon.
Above-mentioned chemical equation has provided the synthetic method of 2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) acetic acid (I) and its optical isomer (II), and its concrete steps are:
A) with 1,2,6,7-tetrahydrochysene-8H-indeno-[5,4-b] furans-8-ketone (1) is starting raw material, there is Wittig-Homer or Wittig condensation reaction with cyanogen methylene phosphonic acid diethyl ester (7) or cyanogen methylene tri phenyl quaternary alkylphosphonium salt (8), obtain (1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-subunit) acetonitrile (2);
Also there is Wittig-Homer or Wittig condensation reaction with 2-(diethoxy phosphonate group) acetic ester (9) or triphenylacetic acid Zhi quaternary alkylphosphonium salt (10) in available compound (1), obtain (1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-subunit) acetic ester (3);
Also available compound (1) and halogenated acetic acids ester (11) are under active zinc powder effect, through Reformatsky condensation reaction, obtain (1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-subunit) acetic ester (3) and 2-hydroxyl-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) mixture of acetic ester (4);
B) by steps A) intermediate (2) that obtains, (3) or/and (4) through catalytic hydrogenation, reduce, obtain 2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) acetonitrile (5) or 2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) acetic ester (6) or (I) (when R is H or benzyl);
C) by step B) intermediate (5) or (6) that obtain are hydrolyzed under acidity or alkaline condition, generate 2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) acetic acid (I);
D) by step C) compound (I) obtaining and the chiral resolving agent salify containing amino, form non-corresponding isomer salt, after separation, through acid neutralization, generate (II) (R or S configuration (I)).
Each step of this synthetic method specifically describes as follows:
Steps A): 1,2,6, there is Wittig-Homer condensation reaction or Wittig condensation reaction with cyanogen methylene phosphonic acid diethyl ester or cyanogen methylene tri phenyl quaternary alkylphosphonium salt in 7-tetrahydrochysene-8H-indeno-[5,4-b] furans-8-ketone (1), make (1 under alkaline condition, 6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-subunit) acetonitrile (2).Wherein, (1) is 1.0:1.0～2.0 with the molar feed ratio of cyanogen methyl-phosphorous acid diethyl ester or cyanogen methylene tri phenyl quaternary alkylphosphonium salt, and preferably molar feed ratio is 1.0:1.1～1.5; Alkali used is the C of basic metal or alkaline earth metal hydroxides, basic metal or alkaline earth metal carbonate, basic metal or alkali metal bicarbonates, basic metal or alkaline-earth metal
1～C
4fat alkoxide, basic metal or alkaline earth metal hydride, butyllithium, preferred bases is: sodium hydride, sodium methylate, sodium ethylate, salt of wormwood; Alkali is 1.0～3.0:1.0 with the molar feed ratio of (1), and preferably molar feed ratio is 1.1～2.0:1.0; Setting-up point is 0 ℃～200 ℃, and preferable reaction temperature is 0 ℃～120 ℃; Reaction times is 1～24 hour, and the preferred reaction time is 2～10 hours;
Under alkaline condition, there is Wittig-Horner or Wittig condensation reaction with 2-(diethoxy phosphonate group) acetic ester or triphenylacetic acid ester quaternary alkylphosphonium salt in starting raw material (1), obtain (1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-subunit) acetic ester (3).Wherein, organophosphorus acetic ester comprises organophosphorus acetic acid, C
1～C
10aliphatic alcohol ester, C
6～C
10phenolic ester, preferably organophosphorus acetic ester is methyl alcohol ester, ethanol ester, phenylcarbinol (benzylalcohol) ester; (1) be 1.0:1.0～2.0 with the molar feed ratio of 2-(diethoxy phosphonate group) acetic ester or triphenylacetic acid Zhi quaternary alkylphosphonium salt, preferably molar feed ratio is 1.0:1.1～1.5; Alkali used is the C of basic metal or alkaline earth metal hydroxides, basic metal or alkaline earth metal carbonate, basic metal or alkali metal bicarbonates, basic metal or alkaline-earth metal
1～C
4fat alkoxide, basic metal or alkaline earth metal hydride, butyllithium, preferred bases is: sodium hydride, sodium methylate, sodium ethylate, salt of wormwood; Alkali is 1.0～3.0:1.0 with the molar feed ratio of (1), and preferably molar feed ratio is 1.1～2.0:1.0; Setting-up point is 0 ℃～150 ℃, and preferable reaction temperature is 0 ℃～50 ℃; Reaction times is 1～24 hour, and the preferred reaction time is 2～10 hours;
Also available starting raw material (1) and halogenated acetic acids ester are under active zinc powder, activator effect, through Reformatsky condensation reaction, obtain (1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-subunit) acetic ester (3) and 2-hydroxyl-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) mixture of acetic ester (4); Wherein, the ester group in halogenated acetic acids ester comprises C
1～C
10aliphatic alcohol ester, C
6～C
10phenolic ester, halogen is Cl, Br, I, and preferably ester is methyl alcohol ester, ethanol ester, phenylcarbinol (benzylalcohol) ester, and preferably halogen is Br; Activator is I
2, CuCl, CuI, MeMgBr, (CH
3)
3siCl, glycol dibromide, preferred active agent I
2, CuCl; (1) be 1.0:1.0～2.0:1.0～2.0 with the molar feed ratio of active zinc powder, halogenated acetic acids ester, preferably molar feed ratio is 1.0:1.5～2.0:1.1～1.5; The solvent that reacts suitable is DMF, tetrahydrofuran (THF), ethyl acetate, ether, toluene, Isosorbide-5-Nitrae-dioxane, glycol dimethyl ether, and preferred solvent is tetrahydrofuran (THF), ether, toluene, Isosorbide-5-Nitrae-dioxane; Setting-up point is 0 ℃～150 ℃, and preferable reaction temperature is 20 ℃～80 ℃; Reaction times is 1～72 hour, and the preferred reaction time is 5～36 hours.
Step B): intermediate (2), (3) or/and (4) in suitable solvent, through catalytic hydrogenation, reduce, by the reduction in molecule or make benzyl position hydroxyl hydrogenolysis, obtain corresponding 2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) acetonitrile (5) or 2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) acetic ester (6) or (I) (when R is H or benzyl).Wherein, catalytic hydrogenation used catalyst is 5%～20%Pd/C, 5%～20%Pd (OH)
2/ C, Raney Ni, preferred catalyst is 10%Pd/C; The solvent that catalytic hydrogenation is suitable is C
1～C
6fatty alcohol, C
1～C
10aliphatic ketone, C
1～C
6lipid acid, DMF, tetrahydrofuran (THF), ethyl acetate, preferred solvent is methyl alcohol, acetic acid, ethyl acetate; Hydrogenation reaction pressure is normal pressure～50 normal atmosphere, and preferred pressure is normal pressure～10 normal atmosphere; Hydrogenation temperature is room temperature～120 ℃, and preferable reaction temperature is room temperature～70 ℃.
Step C): intermediate (5) or (6) are hydrolyzed in acidic aqueous solution, obtain 2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) acetic acid (I).Wherein, acidic aqueous solution used is the mixing solutions that mineral acid (as: hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid), organic acid (as: formic acid, acetic acid, propionic acid, butyric acid, phenylformic acid) or mineral acid and organic carboxyl acid form, the volume ratio of mixed solution is 0.8～1.2:1.0 (mineral acid: organic carboxyl acid), the preferred acidic aqueous solution is hydrochloric acid, hydrochloric acid/acetic acid mixed solution, hydrochloric acid/formic acid mixed solution, and the volume ratio of mixed solution is 1:1; Hydrolysising reacting temperature is room temperature～150 ℃, and preferable reaction temperature is back flow reaction; Hydrolysis time is 1～24 hour, and the preferred reaction time is 2～8 hours.
Intermediate (5) or (6) also can be hydrolyzed under alkaline condition, then, through hydrochloric acid neutralization, obtain 2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) acetic acid (I).Wherein, alkali used is basic metal or alkaline earth metal hydroxides, basic metal or alkaline earth metal carbonate, basic metal or alkali metal bicarbonates, and preferred bases is: sodium carbonate, saleratus; Alkali is 1.0～4.0:1.0 with the molar feed ratio of (5) or (6), and preferably molar feed ratio is 1.1～2.5:1.0; Hydrolysising reacting temperature is room temperature～150 ℃, and preferable reaction temperature is back flow reaction; Hydrolysis time is 1～24 hour, and the preferred reaction time is 1～3 hour.
Step D): racemic 2-(1, 6, 7, 8-tetrahydrochysene-2H-indeno-[5, 4-b] furans-8-yl) acetic acid (I) in suitable solvent with containing amino chiral reagent salify, the diastereoisomeric R of crystallization or S configuration 2-(1, 6, 7, 8-tetrahydrochysene-2H-indeno-[5, 4-b] furans-8-yl) acetic acid ammonium salt (contained 2-(1 in crystalline mother solution, 6, 7, 8-tetrahydrochysene-2H-indeno-[5, 4-b] furans-8-yl) acetic acid ammonium salt is after racemization is processed, recyclable recycling), gained ammonium salt mixes with suitable organic solvent, with aqueous acid, be neutralized to after strongly-acid, separate organic layer (recyclable the recycling of chiral reagent in water layer), organic layer removes solvent under reduced pressure, obtain the 2-(1 of R or S configuration, 6, 7, 8-tetrahydrochysene-2H-indeno-[5, 4-b] furans-8-yl) acetic acid (I), wherein, containing amino chiral reagent, be (S)-α-phenylethylamine, (R)-α-phenylethylamine, (S)-N.N-dimethyl-α-phenylethylamine, (R)-N, N-dimethyl-α-phenylethylamine, D-ephedrine, L-ephedrine, L-(-)-2-amino-1-(4-nitrophenyl)-1, ammediol, D-(+)-2-amino-1-(4-nitrophenyl)-1, ammediol, preferably chiral reagent is (S)-α-phenylethylamine, (R)-α-phenylethylamine; Mole proportioning of chiral reagent and 2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) acetic acid (I) is 0.5～1.5:1.0, and preferred mole of proportioning is 0.6～1.2:1.0; Forming the suitable solvent of ammonium salt is water, C
1～C
6fatty alcohol, ethyl acetate, isopropyl acetate, methylene dichloride, chloroform, C
3～C
10aliphatic ketone, benzene, normal heptane, toluene, preferred solvent is isopropyl acetate, water, methyl alcohol, acetone; Ammonium salt with in acid and time organic solvent used be ether, methylene dichloride, chloroform, ethyl acetate, benzene, normal heptane, toluene, preferred solvent is methylene dichloride, ethyl acetate; In ammonium salt and time mineral acid used be hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid, preferably mineral acid is hydrochloric acid, sulfuric acid.
The common technology in the available this area of starting raw material of the present invention---compound (1) makes, including, but not limited to disclosed method in Publication about Document: 1.Shinichi U, Eigo M, Atsushi I, Takashi O, Shigeharu S.WO2006030739; 2.Osamu U, Kohji F, Ryosuke T.et al.J Med Chem2002,45 (19): 4222-4239; 3.Shigenori O, Osamu U, Kohji F.et al.WO9732871.
The optical isomer (II) that utilizes aforesaid method to make, can be used for preparing insomnia medicine---ramelteon, and its synthetic route is as follows:
The concrete steps of above-mentioned ramelteon synthetic method are:
E) by step D) the Compound I I (that is: (I) of S configuration) that obtains, be converted into after carboxylic acid halides, mixed acid anhydride or active ester and ammonia effect, generate corresponding amide derivatives---(S)-2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) ethanamide (12);
F) by step e) amide compound (12) that obtains, through reduction reaction, (S)-2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) ethamine (13);
G) by step F) ethylamine compounds (13) that obtains, under alkaline condition through the third acylation reaction, (S)-N-[2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) ethyl] propionic acid amide---ramelteon.
E) each step～G) specifically describes as follows:
Step e): (S)-2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) acetic acid (II) is converted into after carboxylic acid halides, mixed acid anhydride or active ester and ammonia react, makes (S)-2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) ethanamide (12).Wherein, described carboxylic acid halides comprises: acyl chlorides, acylbromide; Described mixed acid anhydride comprises: with the mixed acid anhydride of formic acid, acetic acid, propionic acid, methanesulfonic, Phenylsulfonic acid, P-TOLUENE SULFO ACID 99's formation; Described active ester comprises: p-nitrophenyl phenolic ester, pentafluorophenyl esters, pentachlorophenyl ester, N-hydroxy-succinamide ester, HP ester, 1-hydroxy benzo triazole ester; Described ammonia comprises: the aqueous solution of ammonia, ammonia, the alcoholic solution of ammonia or heat are decomposed the compound (as: volatile salt, bicarbonate of ammonia, ammonium acetate etc.) that can discharge ammonia.
Step F): intermediate (12) through chemical reduction, is amino by the reduction of amide in molecule in suitable solvent, obtains accordingly (S)-2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) ethamine (13).Wherein, reductive agent used is BH
3sMe
2, LiAlH
4, NaAlH
4, LiHAl (OMe)
3, NaH
2al (OCH
2cH
2oCH
3)
2, metal borohydride (as: KBH
4, NaBH
4, LiBH
4, NaBH
3cN etc.), the mixture that forms of metal borohydride and acid (comprising: protonic acid, Lewis acid), preferably reductive agent is BH
3sMe
2, LiAlH
4, LiAlH
4-AlCl
3, LiBH
4, NaBH
4-ZnCl
2, NaBH
4-HOAc, NaBH
4-CoCl
2, KBH
4-BF
3et
2o, KBH
4-AlCl
3; Reductive agent is metal hydride with the molar feed ratio of (12): acid: substrate=1.0～10.0:0～10.0:1.0, and preferably molar feed ratio is 1.0～7.0:0～7.0:1.0; The solvent that reduction reaction is suitable is C
1～C
6fatty alcohol, tetrahydrofuran (THF), ether, ethyl acetate, benzene, toluene, Isosorbide-5-Nitrae-dioxane, glycol dimethyl ether, preferred solvent is tetrahydrofuran (THF), toluene, glycol dimethyl ether; Temperature of reaction is-78 ℃～150 ℃, and preferable reaction temperature is 0 ℃～solvent refluxing temperature; The reduction reaction time is 1～72 hour, and the preferred reaction time is 2～24 hours.
Step G): intermediate (13), under suitable solvent and alkaline condition, carries out condensation with the compound of propionyl is provided, and obtains ramelteon.Wherein, condensation reaction alkali used is basic metal or alkaline earth metal hydroxides, basic metal or alkaline earth metal carbonate, basic metal or alkali metal bicarbonates, trimethylamine class or quaternary ammonium bases (as: triethylamine, Tributylamine, trioctylamine, pyridine, N, N-dimethyl-α-phenylethylamine, 4-methylmorpholine, TBAH) or the combination of above-mentioned various alkali, preferred bases is: sodium bicarbonate, salt of wormwood, triethylamine, 4-methylmorpholine; Alkali consumption is 1.0～4.5:1.0 with the molar feed ratio of (13), and preferably molar feed ratio is 1.0～2.0:1.0; The described compound of propionyl that provides comprises: propionic anhydride, propionyl halogenide, propionic acid and condensing agent combination, the mixed acid anhydride of propionic acid are, the p-nitrophenyl phenolic ester of the trinitride of propionic acid or propionic acid, pentafluorophenyl esters, pentachlorophenyl ester, N-hydroxy-succinamide ester, HP ester, 1-hydroxy benzo triazole ester or its combination; (13) be 1.0:1.0～5.0 with the molar feed ratio of the compound of propionyl is provided, preferably molar feed ratio is 1.0:1.0～2.5; During condensation reaction, solvent for use is: ether, tetrahydrofuran (THF), DMF, dimethyl sulfoxide (DMSO), water, C
1～C
6fatty alcohol, ethyl acetate, isopropyl acetate, methylene dichloride, chloroform, C
3～C
8aliphatic ketone, benzene, normal heptane, toluene, preferred solvent is tetrahydrofuran (THF), DMF, water, methylene dichloride, Virahol, acetone, ethyl acetate, toluene; Setting-up point is 0～130 ℃, and preferable reaction temperature is room temperature～80 ℃; Condensation reaction time is 20 minutes～48 hours, and the preferred reaction time is 1～24 hour.
The invention has the advantages that: compared with prior art, the method raw materials used (not needing homogeneous phase chiral catalyst) cheap and easy to get, reaction conditions gentle (not needing High Temperature High Pressure), easy and simple to handle, cost is low, yield is high, " three wastes " pollute less, is applicable to the fairly large ramelteon of preparing.
Embodiment
By the following examples, can conduct further description the present invention, yet scope of the present invention is not limited to following embodiment.One of skill in the art can understand, and is not deviating under the prerequisite of the spirit and scope of the present invention, can carry out various variations and modification to the present invention.
Embodiment 1
The preparation of (1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-subunit) acetonitrile (2)
In reaction flask, add successively cyanogen methylene phosphonic acid diethyl ester 21.27g (0.12mol), 1,2,6,7-tetrahydrochysene-8H-indeno-[5,4-b] furans-8-ketone 17.42g (0.10mol), toluene 120ml and deionized water 60ml, after stirring at room is even, add Tetrabutyl amonium bromide 1.62g (0.005mol) and Anhydrous potassium carbonate 20.70g (0.15mol), be warming up to 60～70 ℃, insulated and stirred reaction 8h; After reaction finishes, be cooled to room temperature, separate toluene layer, toluene 30ml extraction for water layer, combining methylbenzene solution, with saturated NaCl aqueous solution 25ml washing, removes solvent under reduced pressure, resistates recrystallizing methanol, obtain light yellow crystalline solid 17.20g, mp:146～148 ℃, yield 87.2%.
Embodiment 2
The preparation of (1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-subunit) acetonitrile (2)
In reaction flask, add successively cyanogen methylene radical triphen base phosphonium chloride 40.54g (0.12mol), 1, 2, 6, 7-tetrahydrochysene-8H-indeno-[5, 4-b] furans-8-ketone 17.42g (0.10mol) and toluene 200ml, after stirring at room is even, put in ice bath and be cooled to 0～5 ℃, drip 15% methanol solution of sodium methylate (0.13mol), drip and finish, remove ice bath, stirring at room reaction 2.5h, in reaction flask, add deionized water 100ml, stir 30min, by in reaction solution impouring separating funnel, separate organic layer, and wash with saturated NaCl aqueous solution 40ml, remove solvent under reduced pressure, resistates recrystallizing methanol, obtain light yellow crystalline solid 16.51g, mp:145～148 ℃, yield 83.7%.
Embodiment 3
The preparation of (1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-subunit) methyl acetate (3a)
Operating process is with embodiment 1, just by cyanogen methylene phosphonic acid diethyl ester for 2-(diethoxy phosphonate group) methyl acetate substitute, must (1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-subunit) the light yellow oily liquid of methyl acetate, yield 92.1%.Without further refining, be directly used in the next step.
Embodiment 4
The preparation of (1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-subunit) ethyl acetate (3b)
Operating process, with embodiment 2, just substitutes cyanogen methylene radical triphen base phosphonium chloride with ethoxy carbonyl methylene tri phenyl phosphonium bromide, obtain (1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-subunit) the light yellow oily liquid of ethyl acetate, yield 87.9%.Without further refining, be directly used in the next step.
Embodiment 5
The preparation of (1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-subunit) jasmal (3c)
Operating process is with embodiment 1, just by cyanogen methylene phosphonic acid diethyl ester for 2-(diethoxy phosphonate group) jasmal substitute, must (1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-subunit) the yellow oily liquid of jasmal, yield 89.0%.Without further refining, be directly used in the next step.
Embodiment 6
The preparation of 2-hydroxyl-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) ethyl acetate (4a)
Under noble gas protection, in reaction flask, add 1, 2, 6, 7-tetrahydrochysene-8H-indeno-[5, 4-b] furans-8-ketone 17.42g (0.10mol), ethyl bromoacetate 21.71g (0.13mol) and anhydrous tetrahydro furan 300ml, after stirring at room is even, add active zinc powder 11.12g (0.17mol) and catalytic amount iodine, be warming up to 45～50 ℃ of insulated and stirred reaction 24h, after reaction finishes, be cooled to room temperature, filter, filtrate decompression is steamed and is desolventized, in resistates, add ethyl acetate 200ml, use successively 10% aqueous hydrochloric acid 50ml, deionized water 50ml, saturated NaCl aqueous solution 50ml washing, organic layer is through anhydrous Na
2sO
4dry, filter, remove solvent under reduced pressure, obtain dark-brown oily matter 25.13g, yield 95.7%, this mixture is mainly 2-hydroxyl-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) ethyl acetate (4a), containing a small amount of (1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-subunit) ethyl acetate (3b).Without further refining, be directly used in the next step.
Embodiment 7
The preparation of 2-hydroxyl-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) jasmal (4b)
Operating process, with embodiment 6, just substitutes ethyl bromoacetate with benzyl acetate bromide, activator iodine substitutes with CuCl, obtains 2-hydroxyl-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) jasmal, yield 97.0%.This crude product is directly used in the next step.
Embodiment 8
The preparation of 2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) acetonitrile (5)
In reactor, add intermediate (2) 21.0g and methyl alcohol 180ml, after stirring, add 10%Pd/C2.0g, then logical hydrogen reacts 12 hours in 0.5Mpa, stirring at room, after reaction finishes, and filtration catalizer (recovery), a small amount of methanol wash filter cake, filtrate decompression is steamed and is desolventized, and obtains 2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) the light yellow oily liquid 21.0g of acetonitrile, yield 99.0%.
Embodiment 9
The preparation of 2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) methyl acetate (6a)
In reaction flask, add intermediate (3a) crude product 20.0g and acetic acid 120ml, after stirring, add 10%Pd/C2.0g, then logical hydrogen reacts 8h in normal pressure, 55～60 ℃ of insulated and stirred, after reaction finishes, and filtration catalizer (recovery), a small amount of acetic acid washing leaching cake, filtrate decompression is steamed and is desolventized, and obtains 2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) the brown oily liquids 19.8g of methyl acetate, yield 99.0%.
Embodiment 10
The preparation of 2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) ethyl acetate (6b)
Operating process, with embodiment 9, just substitutes intermediate (3a) with intermediate (3b), obtain the brown oily liquids of 2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) ethyl acetate, yield 99.0%.
Embodiment 11
The preparation of 2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) ethyl acetate (6b)
Operating process, with embodiment 9, just substitutes intermediate (3a) with intermediate (4a), obtain the brown oily liquids of 2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) ethyl acetate, yield 96.0%.
Embodiment 12
The preparation of 2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) acetic acid (I)
By 2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) acetonitrile crude product 21.0g (0.1054mol), concentrated hydrochloric acid 100ml and acetic acid 100ml add in reaction flask, temperature rising reflux stirring reaction 8h, after reaction finishes, remove solvent under reduced pressure, resistates ethanol-water mixed solvent recrystallization, obtains white, needle-shaped crystals 19.78g, mp:114～116 ℃, yield 86.0%.
1h NMR (CDCl
3, 400MHz) δ: 11.00 (brs, 1H, COOH), 6.97 (d, J=8.0Hz, 1H, Ar-H), 6.65 (d, J=8.0Hz, 1H, Ar-H), 4.64～4.51 (m, 2H, OCH
2), 3.64～3.57 (m, 1H, CH), 3.26～3.17 (m, 1H, ArCH
2-H
α), 3.15～3.09 (m, 1H, ArCH
2-H
α), 2.96～2.89 (m, 1H, ArCH
2-H
β), 2.83 (q, J
1=4.4Hz, J
2=15.2Hz, 1H, CH
2cOOH), 2.82～2.77 (m, 1H, ArCH
2-H
β), 2.44 (q, J
1=10.2Hz, J
2=15.2Hz, 1H, CH
2cOOH), 2.41～2.35 (m, 1H, CH
2-H
α), 1.95～1.86 (m, 1H, CH
2-H
β);
13c NMR (CDCl
3, 100MHz) δ: 170.95 (C=O), 159.48 (Ar-C
3a), 141.75 (Ar-C
8a), 135.67 (Ar-C
5a), 123.58 (Ar-C
5), 122.11 (Ar-C
8b), 107.88 (Ar-C
4), 71.17 (OCH
2), 40.75 (CH), 38.23 (CH
2cOOH), 32.44 (CH
2-C
6), 30.30 (CH
2-C
1), 28.38 (CH
2-C
7); HR-TOFMS (Q) m/z:217.0860 ([C
13h
14o
3-H]
+calculated value: 217.0865).
Embodiment 13
The preparation of 2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) acetic acid (I)
In reaction flask, add 2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) ethyl acetate 24.63g (0.10mol), ethanol 60ml, deionized water 90ml and sodium carbonate 21.20g (0.20mol), temperature rising reflux stirring reaction 1h, after reaction finishes, be cooled to room temperature, remove ethanol under reduced pressure, residual water solution extracts with ether 2 * 25ml, gained water layer regulates pH to strongly-acid with 10% aqueous hydrochloric acid, with ether 2 * 50ml, extracts, and ether layer is used deionized water 50ml successively, saturated NaCl aqueous solution 25ml washing, organic layer is through anhydrous Na
2sO
4after dry, filter, remove solvent under reduced pressure, obtain white solid 20.45g, mp:114～116 ℃, yield 93.8%.
Embodiment 14
The preparation of 2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) acetic acid (I)
By (1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-subunit) jasmal (3c) crude product 20.0g (0.0653mol) and acetic acid 120ml add in reaction flask, after stirring, add 10%Pd/C2.0g, then logical hydrogen is in normal pressure, 55～60 ℃ of insulated and stirred reaction 8h, after reaction finishes, filtration catalizer (recovery), a small amount of acetic acid washing leaching cake, filtrate decompression is steamed and is desolventized, resistates ethanol-water mixed solvent recrystallization, obtain white, needle-shaped crystals 12.74g, mp:114～116 ℃, yield 89.5%.
Embodiment 15
The preparation of 2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) acetic acid (I)
Operating process is with embodiment 14, just by 2-hydroxyl-(1,6 for intermediate (3c), 7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) jasmal (4b) substitutes, and obtains 2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) white, needle-shaped crystals of acetic acid, mp:114～116 ℃, yield 90.7%.
Embodiment 16
(S) preparation of-2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) acetic acid (II)
In reaction flask, add 2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) acetic acid 21.80g (0.10mol) and acetone 500ml, after stirring, add (R)-α-phenylethylamine 12.12g (0.10mol), temperature rising reflux is entirely molten to solid, be cooled to 45 ℃ of left and right, add a small amount of crystal seed, standing 8 hours of room temperature, filters, obtain (S)-2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) acetic acid-(R)-α-phenylethylamine salt 13.58g, mp:192～194 ℃, yield 40.0%
1.0, MeOH); Gained ammonium salt is suspended in ether 100ml, with 5.0mol/L aqueous hydrochloric acid, is neutralized to strongly-acid, separates ether layer, after anhydrous sodium sulfate drying, remove solvent under reduced pressure, obtain (S)-2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) the white solid 7.92g of acetic acid, mp:108～110 ℃, yield 36.3%
(c1.0, MeOH).
Embodiment 17
(R) preparation of-2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) acetic acid (II)
Fractionation mother liquor in embodiment 16 adds in reaction flask, remove solvent under reduced pressure, in resistates, add deionized water 60ml, obtained aqueous solution is neutralized to strong basicity with the 5%NaOH aqueous solution, with ether 2 * 35ml, extracts, and the water layer separating is neutralized to strongly-acid with 10% aqueous hydrochloric acid, with ether 2 * 35ml, extract, ether layer is used deionized water 25ml successively, saturated NaCl aqueous solution 25ml washing, and organic layer is through anhydrous Na
2sO
4after dry, filter, remove solvent under reduced pressure, residual solid is dissolved in 300 milliliters, acetone, adds (S)-α-phenylethylamine 7.72g (0.064mol), and temperature rising reflux is entirely molten to solid, be cooled to 45 ℃ of left and right, add a small amount of crystal seed, standing 8 hours of room temperature, filter, obtain (R)-2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) acetic acid-(S)-α-phenylethylamine salt 12.91g, mp:188～192 ℃, yield 38.0%
(c1.0, MeOH); Gained ammonium salt is suspended in ether 100ml, with 5.0mol/L aqueous hydrochloric acid, is neutralized to strongly-acid, separates ether layer, after anhydrous sodium sulfate drying, remove solvent under reduced pressure, obtain (R)-2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) the white solid 7.16g of acetic acid, mp:108～110 ℃, yield 32.8%
(c1.0, MeOH).
Embodiment 18
(S) preparation of-2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) ethanamide (12)
By (S)-2-(1, 6, 7, 8-tetrahydrochysene-2H-indeno-[5, 4-b] furans-8-yl) acetic acid 21.83g (0.10mol), the N of chloroform 210ml and catalytic amount, dinethylformamide adds in reaction flask, after stirring at room is even, drip thionyl chloride 17.85g (0.15mol), drip and finish, temperature rising reflux stirring reaction 1.5h, after reaction finishes, be cooled to room temperature, this mixed solution is slowly added dropwise in ice-cold strong aqua 40ml, stirring at room 5h, remove solvent under reduced pressure, residual solid ethanol-water mixed solvent recrystallization, obtain (S)-2-(1, 6, 7, 8-tetrahydrochysene-2H-indeno-[5, 4-b] furans-8-yl) the white, needle-shaped crystals 18.95g of ethanamide, mp:214～216 ℃, yield 87.2%.
1h NMR (DMSO-d
6, 400MHz) δ: 7.35 (brs, 1H, NH), 6.91 (d, J=8.4Hz, 1H, Ar-H), 6.84 (brs, 1H, NH), 6.51 (d, J=8.4Hz, 1H, Ar-H), 4.53～4.41 (m, 2H, OCH
2), 3.45～3.40 (m, 1H, CH), 3.22～3.15 (m, 1H, ArCH
2-H
α), 3.12～3.09 (m, 1H, ArCH
2-H
α), 2.84～2.75 (m, 1H, ArCH
2-H
β), 2.70～2.66 (m, 1H, ArCH
2-H
β), 2.48～2.42 (m, 1H, CH
2-H
α), 2.20～2.05 (m, 2H, CH
2cO), 1.77～1.70 (m, 1H, CH
2-H
β); HR-TOFMS (+Q) m/z:240.0995 ([C
13h
15nO
2+ Na]
+calculated value: 240.1000).
Embodiment 19
(S) preparation of-2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) ethylamine hydrochloride (13)
In the reaction flask of drying tube and logical argon gas is housed, add Lithium Aluminium Hydride 1.90g (0.05mol) and 50ml anhydrous tetrahydro furan, stirring at room 10min, drips (S)-2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) ethanamide 10.87g (0.05mol) is dissolved in the solution of 50ml anhydrous tetrahydro furan, control splashes into speed, make the micro-backflow of reaction solution, drip and finish, continue return stirring reaction 2h; After reaction finishes, be cooled to room temperature, add a small amount of ethyl acetate to decompose superfluous Lithium Aluminium Hydride, remove solvent under reduced pressure, in resistates, add 20% aqueous sodium hydroxide solution 30ml, with ethyl acetate 2 * 50ml, extract, organic layer merges, with 10% aqueous hydrochloric acid, be neutralized to strongly-acid, remove solvent under reduced pressure, acetone for residual solid-methanol mixed solvent recrystallization, obtains white crystals 10.26g, mp:262～265 ℃ (dec.), yield 85.6%.
1h NMR (DMSO-d
6, 400MHz) δ: 8.05 (brs, 2H, NH
2), 6.92 (d, J=8.4Hz, 1H, Ar-H), 6.54 (d, J=8.4Hz, 1H, Ar-H), 4.58～4.41 (m, 2H, OCH
2), 3.24～3.06 (m, 3H, CH, CH
2nH
2), 2.86～2.65 (m, 4H, 2 * ArCH
2), 2.25～2.05 (m, 2H, CH
2), 1.77～1.61 (m, 2H, CH
2); HR-TOFMS (+Q) m/z:204.1398 ([C
13h
18clNO-Cl]
+calculated value: 204.1388).
Embodiment 20
(S) preparation of-2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) ethylamine hydrochloride (13)
In the reaction flask of reflux condensing tube, drying tube is housed, add tetrahydrofuran (THF) 50ml, ice bath is cooling, under argon shield, adds AlCl
329.7g (0.22mol) and KBH
412.0g (0.22mol), after stirring at room reaction 1h, add (S)-2-(1, 6, 7, 8-tetrahydrochysene-2H-indeno-[5, 4-b] furans-8-yl) ethanamide 19.35g (0.089mol), stirring at room is reacted 1h again, progressively temperature rising reflux reacts 12h, reclaim under reduced pressure tetrahydrofuran (THF), resistates is hydrolyzed with 10% aqueous hydrochloric acid 150ml, chloroform 50ml extraction for the aqueous solution, with 20% aqueous sodium hydroxide solution, regulate pH to 11～12 again, with ethyl acetate 2 * 50ml, extract, organic layer merges, with 10% aqueous hydrochloric acid, be neutralized to strongly-acid, remove solvent under reduced pressure, acetone for residual solid-methanol mixed solvent recrystallization, obtain white crystals 19.15g, mp:264～266 ℃ (dec.), yield 89.8%.
Embodiment 21
(S)-N-[2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) ethyl] propionic acid amide (ramelteon) synthetic
In reaction flask, add (S)-2-(1, 6, 7, 8-tetrahydrochysene-2H-indeno-[5, 4-b] furans-8-yl) ethylamine hydrochloride 7.20g (0.03mol), tetrahydrofuran (THF) 30ml and pyridine 7.91g (0.1mol), after stirring at room is even, put in ice bath and be cooled to 0～10 ℃, add propionic anhydride 5.86g (0.045mol), then stirring at room is reacted 1h, after reaction finishes, remove solvent under reduced pressure, in resistates with frozen water 50ml, stir 10min, filter, gained filter cake ethanol-water mixed solvent recrystallization, obtain the white, needle-shaped crystals 7.51g of ramelteon, mp:114～115 ℃, yield 96.5%,
1h NMR (CDCl
3, 400MHz) β: 6.95 (d, J=8.0Hz, 1H, Ar-H), 6.61 (d, J=8.0Hz, 1H, Ar-H), 5.45 (brs, 1H, CONH), 4.62～4.48 (m, 2H, OCH
2), 3.39～3.06 (m, 5H, CH, CH
2nH
2, ArCH
2), 2.93～2.85 (m, 1H, ArCH
2-H
β), 2.81～2.73 (m, 1H, ArCH
2-H
β), 2.32～2.24 (m, 1H, CH
2-H
α), 2.17 (q, J=7.6Hz, 2H, CH
2cH
3), 2.06～1.98 (m, 1H, CH
2-H
α), 1.86～1.78 (m, 1H, CH
2-H
α), 1.68～1.59 (m, 1H, CH
2-H
β), 1.14 (t, J=7.6Hz, 3H, CH
2cH
3), HR-TOFMS (+Q) m/z:260.1660 ([C
16h
21nO
2+ H]
+calculated value: 260.1651).
Embodiment 22
(S)-N-[2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) ethyl] propionic acid amide (ramelteon) synthetic
In reaction flask, add (S)-2-(1, 6, 7, 8-tetrahydrochysene-2H-indeno-[5, 4-b] furans-8-yl) ethylamine hydrochloride 4.80g (0.02mol), tetrahydrofuran (THF) 20ml and triethylamine 4.05g (0.04mol), after stirring at room is even, put in ice bath and be cooled to 0～10 ℃, add N-hydroxy-succinamide propionyl ester 3.77g (0.022mol), then stirring at room is reacted 5h, after reaction finishes, remove solvent under reduced pressure, in resistates with frozen water 50ml, stir 10min, filter, gained filter cake ethanol-water mixed solvent recrystallization, obtain the white, needle-shaped crystals 4.70g of ramelteon, mp:114～115 ℃, yield 90.8%,
Claims (8)
1. a method of preparing ramelteon, is characterized in that comprising the steps:
A) with 1,2,6,7-tetrahydrochysene-8H-indeno-[5,4-b] furans-8-ketone (1) for starting raw material, with cyanogen methylene phosphonic acid diethyl ester (7) or cyanogen methylene tri phenyl season
there is Wittig-Horner or Wittig condensation reaction in salt (8), obtains (1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-subunit) acetonitrile (2);
Or with compound (1) and halogenated acetic acids ester (11) under active zinc powder effect, through Reformatsky condensation reaction, obtain (1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-subunit) acetic ester (3) and 2-hydroxyl-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) mixture of acetic ester (4);
B) by steps A) intermediate (2) that obtains, (3) be or/and (4), through catalytic hydrogenation reduction, obtain 2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) acetonitrile (5) or 2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) acetic ester (6), or when being H or benzyl, R obtains racemization 2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) acetic acid (I);
C) by step B) intermediate (5) or (6) that obtain are hydrolyzed under acidity or alkaline condition, generate racemization 2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) acetic acid (I);
D) by step C) compound (I) raceme obtaining and the chiral resolving agent salify in suitable solvent containing amino, form non-corresponding isomer salt, after separation, through acid neutralization, generate the compound (I) of R or S configuration; Wherein, containing amino chiral resolving agent, be: (S)-α-phenylethylamine, (R)-α-phenylethylamine, (S)-N, N-dimethyl-α-phenylethylamine, (R)-N, N-dimethyl-α-phenylethylamine, D-ephedrine, L-ephedrine, L-(-)-2-amino-1-(4-nitrophenyl)-1, ammediol, D-(+)-2-amino-1-(4-nitrophenyl)-1,3-PD;
E) by step D) the S configuration of compound (I) that obtains, be converted into after carboxylic acid halides, mixed acid anhydride or active ester and ammonia effect, generate (S)-2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) ethanamide (12);
F) by step e) acetamide compound (12) that obtains, through reduction reaction, (S)-2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) ethamine (13);
G) by step F) ethylamine compounds (13) that obtains, through the third acylation reaction, (S) N-[2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) ethyl] propionic acid amide---ramelteon,
2. ramelteon preparation method as claimed in claim 1, is characterized in that described steps A) in, compound (1) and cyanogen methyl-phosphorous acid diethyl ester or cyanogen methylene tri phenyl season
the molar feed ratio of salt is 1.0: 1.0～2.0; Alkali used is the C of basic metal or alkaline earth metal hydroxides, basic metal or alkaline earth metal carbonate, basic metal or alkali metal bicarbonates, basic metal or alkaline-earth metal
1～C
4fat alkoxide, basic metal or alkaline earth metal hydride, butyllithium; Alkali is 1.0～3.0: 1.0 with the molar feed ratio of (1); Setting-up point is 0 ℃～200 ℃; Reaction times is 1～24 hour;
Compound (1) is 1.0: 1.0～2.0: 1.0～2.0 with the molar feed ratio of active zinc powder, halogenated acetic acids ester; The solvent that reacts suitable is DMF, tetrahydrofuran (THF), ethyl acetate, ether, toluene, Isosorbide-5-Nitrae-dioxane, glycol dimethyl ether; Setting-up point is 0 ℃～150 ℃; Reaction times is 1～72 hour.
3. the preparation method of ramelteon as claimed in claim 1, is characterized in that described step B) in, catalytic hydrogenation used catalyst is 5%～20%Pd/C, 5%～20%Pd (OH)
2/ C, Raney Ni; Catalytic hydrogenation solvent for use is C
1～C
6fatty alcohol, C
1～C
10aliphatic ketone, C
1～C
6lipid acid, DMF, tetrahydrofuran (THF), ethyl acetate; Hydrogenation reaction pressure is normal pressure～50 normal atmosphere; Hydrogenation temperature is room temperature～120 ℃.
4. the preparation method of ramelteon as claimed in claim 1, it is characterized in that described step C) in, acidic aqueous solution used is the mixing solutions that mineral acid, organic acid or mineral acid and organic carboxyl acid form, and the volume ratio of mixed solution is mineral acid: organic carboxyl acid=0.8～1.2: 1.0; Hydrolysising reacting temperature is room temperature～150 ℃; Hydrolysis time is 1～24 hour; Alkali used is basic metal or alkaline earth metal hydroxides, basic metal or alkaline earth metal carbonate, basic metal or alkali metal bicarbonates; Alkali is 1.0～4.0: 1.0 with the molar feed ratio of (5) or (6); Hydrolysising reacting temperature is room temperature～150 ℃; Hydrolysis time is 1～24 hour.
5. the preparation method of ramelteon as claimed in claim 1, is characterized in that described step D) in, containing amino chiral resolving agent and racemization 2-(1,6,7,8-tetrahydrochysene-2H-indeno-[5,4-b] furans-8-yl) mole proportioning of acetic acid (I) is 0.5～1.5: 1.0; Forming ammonium salt solvent for use is water, C
1～C
6fatty alcohol, ethyl acetate, isopropyl acetate, methylene dichloride, chloroform, C
3～C
10aliphatic ketone, benzene, normal heptane or toluene.
6. the preparation method of ramelteon as claimed in claim 1, is characterized in that described step e) in, carboxylic acid halides is acyl chlorides, acylbromide; Mixed acid anhydride is the mixed acid anhydride forming with formic acid, acetic acid, propionic acid, methanesulfonic, Phenylsulfonic acid, P-TOLUENE SULFO ACID 99; Active ester is p-nitrophenyl phenolic ester, pentafluorophenyl esters, pentachlorophenyl ester, N-hydroxy-succinamide ester, HP ester, 1-hydroxy benzo triazole ester; Described ammonia is that the aqueous solution of ammonia, ammonia is, the alcoholic solution of ammonia or heat are decomposed the compound that can discharge ammonia.
7. the preparation method of ramelteon as claimed in claim 1, is characterized in that described step F) in, reductive agent used is BH
3sMe
2, LiAlH
4, NaAlH
4, LiHAl (OMe)
3, NaH
2al (OCH
2cH
2oCH
3)
2, the mixture that forms of metal borohydride, metal borohydride and acid; Reductive agent is metal hydride with the molar feed ratio of (12): acid: substrate=1.0～10.0: 0～10.0: 1.0; The solvent that reduction reaction is suitable is C
1～C
6fatty alcohol, tetrahydrofuran (THF), ether, ethyl acetate, benzene, toluene, Isosorbide-5-Nitrae-dioxane, glycol dimethyl ether; Temperature of reaction is-78 ℃～150 ℃; The reduction reaction time is 1～72 hour.
8. the preparation method of ramelteon as claimed in claim 1, it is characterized in that described step G) in, condensation reaction alkali used is the combination of basic metal or alkaline earth metal hydroxides, basic metal or alkaline earth metal carbonate, basic metal or alkali metal bicarbonates, trimethylamine class or quaternary ammonium bases or above-mentioned various alkali; Alkali consumption is 1.0～4.5: 1.0 with the molar feed ratio of (13); The described compound of propionyl that provides comprises: propionic anhydride, propionyl halogenide, propionic acid and condensing agent combination, the mixed acid anhydride of propionic acid are, the p-nitrophenyl phenolic ester of the trinitride of propionic acid or propionic acid, pentafluorophenyl esters, pentachlorophenyl ester, N-hydroxy-succinamide ester, HP ester, 1-hydroxy benzo triazole ester or its combination; (13) be 1.0: 1.0～5.0 with the molar feed ratio of the compound of propionyl is provided; During condensation reaction, solvent for use is: ether, tetrahydrofuran (THF), DMF, dimethyl sulfoxide (DMSO), water, C
1～C
6fatty alcohol, ethyl acetate, isopropyl acetate, methylene dichloride, chloroform, C
3～C
8aliphatic ketone, benzene, normal heptane, toluene; Setting-up point is 0～130 ℃; Condensation reaction time is 20 minutes～48 hours.
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| WO2010041271A2 (en) * | 2008-09-16 | 2010-04-15 | Usv Limited | Process for preparation of (s)-n-[2-(1,6,7,8-tetrahydro-2h-indeno[5,4-b]furan-8-yl)ethyl] propionamide and novel intermediates thereof |
| CN102070576B (en) * | 2011-01-12 | 2012-11-28 | 四川大学 | 1-indanone-3-acetic acid compound as well as preparation method and application of 1-indanone-3-acetic acid compound |
| CN102321056B (en) * | 2011-07-29 | 2014-05-14 | 宁波人健药业集团股份有限公司 | Method for synthesizing Ramelteon |
| CN102358733B (en) * | 2011-09-01 | 2013-03-27 | 四川大学 | 2-(1-oxy-1H-indene-3-radical) acetic acid compound and preparation method and application thereof |
| CN103570651B (en) * | 2012-07-30 | 2016-04-27 | 北京万生药业有限责任公司 | A kind of method preparing ramelteon intermediate |
| CN103664849B (en) * | 2012-08-31 | 2017-03-29 | 上海阳帆医药科技有限公司 | Prepare the 2 (methods of 1,6,7,8 tetrahydrochysene 2H indenos [5,4 b] furan, 8 subunit ethamine |
| CN103880794B (en) * | 2012-12-21 | 2017-03-22 | 上海阳帆医药科技有限公司 | Preparation method for key intermediate of ramelteon |
| CN104109143B (en) * | 2013-04-22 | 2018-04-27 | 上海阳帆医药科技有限公司 | A kind of melatonin (MT1-MT2) receptor stimulating agent and preparation method thereof and purposes |
| CN105622557B (en) * | 2014-11-05 | 2018-12-04 | 上海医药工业研究院 | Ramelteon intermediate and preparation method thereof |
| CN106749131B (en) * | 2015-11-20 | 2019-03-08 | 上海医药工业研究院 | Racemization prepares ramelteon intermediate method |
| CN109651313B (en) * | 2019-01-28 | 2021-02-19 | 四川大学 | Chiral 2,3-dihydrobenzofuran derivative and preparation method thereof |
| KR102359229B1 (en) * | 2020-04-16 | 2022-02-07 | 제이투에이치바이오텍 (주) | A method for manufacturing ramelteon and intermediate compounds used therein |
| CN113087622B (en) * | 2021-03-15 | 2023-03-31 | 广州一品红制药有限公司 | Preparation method of eptazocine intermediate |
| CN115093392B (en) * | 2022-06-21 | 2024-04-30 | 苏州富士莱医药股份有限公司 | Preparation method of R-lipoic acid |
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| Title |
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| Disclosed Anonymously.Intermediates of (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethyl]propionamide.《http://priorartdatabase.com/ipcom/000170556#》.2008, * |
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