CN1266105C - 4-苯丁酸的合成 - Google Patents
4-苯丁酸的合成 Download PDFInfo
- Publication number
- CN1266105C CN1266105C CNB028102649A CN02810264A CN1266105C CN 1266105 C CN1266105 C CN 1266105C CN B028102649 A CNB028102649 A CN B028102649A CN 02810264 A CN02810264 A CN 02810264A CN 1266105 C CN1266105 C CN 1266105C
- Authority
- CN
- China
- Prior art keywords
- formula
- catalyzer
- benzene
- compound
- mixture
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- OBKXEAXTFZPCHS-UHFFFAOYSA-N 4-phenylbutyric acid Chemical compound OC(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-N 0.000 title abstract description 21
- 229950009215 phenylbutanoic acid Drugs 0.000 title abstract description 7
- 230000015572 biosynthetic process Effects 0.000 title 1
- 238000003786 synthesis reaction Methods 0.000 title 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims abstract description 48
- 150000001875 compounds Chemical class 0.000 claims abstract description 39
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 28
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 16
- 229930188620 butyrolactone Natural products 0.000 claims abstract description 14
- 239000003054 catalyst Substances 0.000 claims abstract description 11
- 239000002841 Lewis acid Substances 0.000 claims abstract description 5
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 22
- 239000000243 solution Substances 0.000 claims description 11
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 8
- 239000011541 reaction mixture Substances 0.000 claims description 8
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 239000008346 aqueous phase Substances 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- -1 alkali metal cation Chemical class 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- 229910015900 BF3 Inorganic materials 0.000 claims description 4
- 229910021626 Tin(II) chloride Inorganic materials 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 229910052742 iron Inorganic materials 0.000 claims description 4
- 239000012074 organic phase Substances 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 235000011150 stannous chloride Nutrition 0.000 claims description 4
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 claims description 4
- 239000011592 zinc chloride Substances 0.000 claims description 4
- 235000005074 zinc chloride Nutrition 0.000 claims description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 3
- 125000000304 alkynyl group Chemical group 0.000 claims description 3
- QFXZANXYUCUTQH-UHFFFAOYSA-N ethynol Chemical group OC#C QFXZANXYUCUTQH-UHFFFAOYSA-N 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000002769 thiazolinyl group Chemical group 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims 2
- 239000001257 hydrogen Substances 0.000 claims 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- 239000002585 base Substances 0.000 abstract 2
- 238000006386 neutralization reaction Methods 0.000 abstract 2
- 150000001491 aromatic compounds Chemical class 0.000 abstract 1
- 239000002904 solvent Substances 0.000 description 11
- 239000003795 chemical substances by application Substances 0.000 description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229960001701 chloroform Drugs 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 230000006353 environmental stress Effects 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- GPRLSGONYQIRFK-UHFFFAOYSA-N hydron Chemical group [H+] GPRLSGONYQIRFK-UHFFFAOYSA-N 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- QJHOLCUPMFGSTI-UHFFFAOYSA-N 4-phenylbutanoic acid;hydrochloride Chemical compound Cl.OC(=O)CCCC1=CC=CC=C1 QJHOLCUPMFGSTI-UHFFFAOYSA-N 0.000 description 1
- OBKXEAXTFZPCHS-UHFFFAOYSA-M 4-phenylbutyrate Chemical compound [O-]C(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-M 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 201000003883 Cystic fibrosis Diseases 0.000 description 1
- 108010044495 Fetal Hemoglobin Proteins 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 102000010029 Homer Scaffolding Proteins Human genes 0.000 description 1
- 108010077223 Homer Scaffolding Proteins Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 206010020575 Hyperammonaemia Diseases 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- JFLIEFSWGNOPJJ-JTQLQIEISA-N N(2)-phenylacetyl-L-glutamine Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)CC1=CC=CC=C1 JFLIEFSWGNOPJJ-JTQLQIEISA-N 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- 208000000599 Ornithine Carbamoyltransferase Deficiency Disease Diseases 0.000 description 1
- 208000035903 Ornithine transcarbamylase deficiency Diseases 0.000 description 1
- 241001310793 Podium Species 0.000 description 1
- 241000287531 Psittacidae Species 0.000 description 1
- SKZKKFZAGNVIMN-UHFFFAOYSA-N Salicilamide Chemical compound NC(=O)C1=CC=CC=C1O SKZKKFZAGNVIMN-UHFFFAOYSA-N 0.000 description 1
- 208000002903 Thalassemia Diseases 0.000 description 1
- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000001667 episodic effect Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 235000013569 fruit product Nutrition 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- SCEZYJKGDJPHQO-UHFFFAOYSA-M magnesium;methanidylbenzene;chloride Chemical compound [Mg+2].[Cl-].[CH2-]C1=CC=CC=C1 SCEZYJKGDJPHQO-UHFFFAOYSA-M 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 201000011278 ornithine carbamoyltransferase deficiency Diseases 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 108010033586 polyethylene glycol-glutaminase-asparaginase Proteins 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000108 silver(I,III) oxide Inorganic materials 0.000 description 1
- PODWXQQNRWNDGD-UHFFFAOYSA-L sodium thiosulfate pentahydrate Chemical compound O.O.O.O.O.[Na+].[Na+].[O-]S([S-])(=O)=O PODWXQQNRWNDGD-UHFFFAOYSA-L 0.000 description 1
- RHLFTMGPBSLHRS-UHFFFAOYSA-M sodium;2-phenylbutanoate Chemical compound [Na+].CCC(C([O-])=O)C1=CC=CC=C1 RHLFTMGPBSLHRS-UHFFFAOYSA-M 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/353—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by isomerisation; by change of size of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Catalysts (AREA)
Abstract
一种式(I)化合物的合成方法:式(I)通过芳族化合物与丁内酯反应,随后用碱中和。该反应可在催化存在下进行。优选的催化剂为路易斯酸。式I的一个优选产品为4-苯丁酸,其通过苯与丁内酯在氯化铝催化下反应、随后用碱中和得到。
Description
发明背景
本发明涉及式I化合物的一种新的合成方法。
式I
苯丁酸及其药学上可接受的衍生物是本发明特别优选的目标。苯丁酸钠已经广泛地用于治疗尿素循环紊乱(Batshaw等人,Brusilow等人(Ped.Research),Brusilow等人(New Eng.J.Med.),Finkelstein等人,Maestri等人,Redonnet-Vernhet等人,Rowe等人)。苯丁酸盐衍生物已经在镰状细胞血症(Collins等人,Dover等人(New Eng.J.Med),Dover等人(Blood))、囊肿性纤维化(Bradbury等人,Loffing等人)、爱滋病(Roberts等人)和几种癌症(Carducci等人,Darmanun等人,Englehard等人,Gorospe等人)的治疗方面显示出有希望的药物特性。
过去,苯丁酸盐衍生物已经通过使用重氮甲烷与氧化银和硫代硫酸钠的Amdt-Einstert反应(J.Chem.Soc.,1997-99(1938))制备。做为选择,硫茚(thianapthene)-2-乙酸和thianapthene-3-乙酸已经用于制备β-苯丁酸(J.Am.Chem.Soc.,70,3768(1948))。在苯丁酸的合成中还使用了格氏试剂、氯化苄基镁,得到的产率为16.1%(J.Am.Chem.Soc.,71,2807-2808(1949))。
有这样一条苯丁酸盐及其衍生物的合成路线将是很有利的:其不受合成限制的阻碍,即从重氮甲烷和格氏试剂中必须除去水分的需要,因而比上述反应产率更高。
发明概述
本发明的一个方面是一种式I化合物的制备方法:
式I
其中R独立地选自氢原子、卤原子、C1-C4烷基、烯基、炔基、C3-C6环烷基、C1-C4烷氧基、链烯氧基、链炔氧基;X为氢离子、碱金属阳离子、铵基或取代铵基。根据本发明的一个实施方案,该方法包括步骤,
a)式II化合物与式III化合物反应;
式II
其中R定义如上;和
式III
b)将得到的化合物与式IV化合物反应;
Xb-Zc
式IV
其中X定义如上,Z为羟基、硫酸根、磷酸根、碳酸氢根、碳酸根或烷氧基,b和C独立地为1-5。式IV化合物特别优选为氢氧化钠。
根据本发明的一个方面,式II化合物与式III化合物的反应在催化剂存在下进行。特别优选为路易斯酸,非限制性地包括氯化铝、氯化锌、氯化铁、氯化亚锡、三氟化硼或硫酸。
本发明的一种优选方面为通过苯与丁内酯反应制备4-苯丁酸的方法。其中一个方案是,苯和催化剂的混合物在与丁内酯反应之前一起搅拌1分钟至15分钟;苯和催化剂的混合物在加入丁内酯之前在50℃至60℃下进行搅拌;包含苯、催化剂和丁内酯的反应混合物搅拌30分钟至120分钟。
式I化合物的制备方法进一步包括步骤:
c)过滤步骤b)的溶液以从水溶液中除去固体,
d)将步骤c)的溶液与有机溶剂接触以得到有机相和水相,
e)将水相与有机相中分离,
f)将酸加入到水相中以降低水相的pH值,加入量足以从水相中沉淀出产品,和
g)从水相中分离出产品。
发明详述
根据下面的描述和说明实施例本领域技术人员可以清楚本发明为式I化合物的合成方法:
式I
其中R独立地选自氢原子、卤原子、C1-C4烷基、烯基、炔基、C3-C6环烷基、C1-C4烷氧基、链烯氧基、链炔氧基;X是氢离子、碱金属阳离子、铵基或取代铵基。
毫无疑问应当理解在任何实际实施方案的发展过程中必须作出许多具体实施决定以实现开发者具体的具体目标—例如符合与体制有关和业务有关的限制—其会各有差异。此外,应当理解这种开发工作可能是复杂和耗时的,但是对于本领域普通技术人员而言仍然是属于本发明的常规手段。
本发明的方法包括步骤a)式II化合物与式III化合物反应。
式II
式III
式II特别优选为苯。根据本发明的一个实施方案,该反应在溶剂中进行。根据另一个实施方案,式II化合物本身为反应的溶剂。
可以用催化剂来促进式II化合物与式III化合物的反应。催化剂的种类优选为路易斯酸。特别优选的催化剂实例为氯化铝、氯化锌、氯化铁、氯化亚锡、三溴化硼、三氟化硼和硫酸。
根据本发明的一个实施方案,将催化剂加入到式II化合物和适当溶剂的混合物中或加入到纯式II化合物中—如果不使用溶剂的话。混合物—优选伴随搅拌—保持在约-80℃和环境压力溶剂的沸点之间的温度。混合物优选保持在0℃和溶剂沸点之间。式II化合物和催化剂的混合物可以在式III化合物加入到该混合物之前搅拌数秒至数天。式II化合物和催化剂的混合物在式III化合物加入之前优选搅拌1min至约30min。其中一个方案是,包含式II化合物和氯化铝的混合物在40℃至60℃一起搅拌10分钟,随后加入式III化合物。
式III化合物可以作为纯的反应物加入到式II化合物和催化剂的混合物中,或可以作为适当溶剂中的溶液加入。式III化合物以小的等分量或大的分量滴加。在式III化合物的加入完成之后,反应混合物—优选伴随搅拌—保持在约-80℃和环境压力下溶剂的沸点之间的温度。混合物优选保持在0℃和溶剂沸点之间。反应混合物可以这样保持数秒至约24小时。反应混合物优选保持约10min至约180min,更优选约60min至约120min。其中一个方案是,式III化合物与包含式II化合物和氯化铝的混合物在50℃至60℃一起搅拌90分钟,随后加入氢氧化钠。
反应混合物可通过加入停止剂停止。适当的停止剂为式IV:
Xb-Zc
式IV
其中X定义如上,Z为羟基、硫酸根、磷酸根、碳酸氢根、碳酸根或烷氧基,b和c独立地为1-5。停止剂可以纯净形式或作为适当溶剂中的溶液加入。特别优选的停止剂为碱的水溶液。优选的碱为氢氧化钠。另一种优选的停止剂为碱的水溶液和冰的混合物。
该停止溶液可以保持在约0至约50℃数分钟至约10小时,优选约1小时至约3小时。溶液的pH值可保持在约6.5至约10,优选约9至约9.5。溶液的pH值可以通过加入碱进一步提高。停止溶液可以通过过滤提纯以除去任何可能存在的颗粒。停止溶液可能进一步通过将其与有机溶剂接触进行提纯,从而萃取出其余原料、副产品和杂质。适当萃取剂的实例包括氯仿、二氯甲烷、三氯甲烷、四氯化碳和乙醚。产品可通过加入酸从水溶液中沉淀出来。产物可以通过过滤或萃取到适当有机溶剂中进行分离。如果产品萃取到有机溶剂中,其可以通过蒸发溶剂进行回收。
下列实施例用以说明本发明的优选实施方案。本领域技术人员应该理解随后的实施例所公开的方法代表了本发明人在本发明的实施中找到的作用良好的方法,并因此可以认为构成了其实施的优选方式。然而,根据本发明,本领域技术人员应该理解可在公开的具体实施方案中作许多改变仍然得到相同或类似的结果而不背离本发明的精神和范围。
实施例1
将粉末氯化铝(200g)加入到苯(400g)中并且在50℃搅拌10min。丁内酯(86g)分批加入。温度在50至60℃保持90min,然后边搅拌边将反应混合物加入到冰和5%氢氧化钠的混合物中。温度在35℃以下且pH值在9至9.5保持2小时。混合物在真空下过滤。通过加入冰和盐酸将苯丁酸从含水部份中沉淀出来。粗(93.7%-94.3%)4-苯丁酸通过真空过滤进行分离。
粗4-苯丁酸通过真空蒸馏(120-125℃,1mm Hg)提纯。该酸溶于5%的氢氧化钠中并进行搅拌。该酸溶于5%氢氧化钠中并与四氯化碳一起搅拌15分钟。除去四氯化碳然后将苯丁酸溶液在室温下与丙酮、甲醇和少量活性炭混合15分钟。混合物通过加入HCl进行过滤和酸化。将4-苯丁酸晶体(产率81.15%)分离并且通过冷冻干燥法干燥。HPLC分析显示该最终产物的纯度为99.87%。
所有本发明说明书和权利要求书中的方法根据本发明而没有不当的实验方法可以进行和实施。本发明的组合物和方法已经用优选实施方案进行了描述,本领域技术人员改变本发明中描述的方法和步骤或该方法步骤的排序而不背离本发明的原则、精神和范围是显而易见的。更具体地说,某些化学性质和生理学性质都相关的试剂可用来替代此处描述的试剂而获得相同的或类似的结果,这应当是显而易见的。所有这些对本领域技术人员显而易见的相似替代和改进被认为落在如所附权利要求书所限定的本发明的精神、范围和原则之内。
参考文献
下列参考文献—在一定程度上它们提供典型的过程或是那些此处列出的文献的其他详细补充—此处具体地引入作为参考。
Carducci M.A.,Nelson J.,Chan-Tack K.,Ayyagari S.R.,SweattW.,Campbell P.,Nelson W.,Simons J.Phenylbutyrate InducesApoptosis in Human Prostate Cancer Therapy and is More Potentthan Phenylacetate.Podium Presentation,American UrologicalAssociation,Las Vegas,NV.April,1995.Clinical Cancer Research2:379-387.1996.
Damanun D.,Welch S.,Rini A.,et al Phenylbutyrate-inducedGlutamine Depletion in Humans:Effect on Leucine Metabolism.AmJ Physiol 274(5 Pt 1):E801-7.May 1998.
Englehard H.,Homer R.J.,Duncan H.,Rozental J.InhibitoryEffects of Phenylbutyrate on the Proliferation,Morphology,Migration and Invasiveness of Malignant Glioma Cells.J.Neuro-Oncology.37:97-108.1998.
Roberts J,McGregor W.G.Inhibition of Mouse RetroviralDisease by Bioactive Glutaminaseasparaginase J.Gen.Virol.72:299-305.1991.
Bradbury N.A.,Focus on ″Sodium 4-phenylbutyrateDownregulates Hsc 70:Implications for Int racellular Traffickingof DF508-CFTR.″Am J Physiol Cell Physiol 278(2):C257-8.Feb2000.
Loffing J.,Moyer B.D.,Reynolds D.,Stanton B.A.,PBAIncreases CFTR Expression but at High Doses Inhibits Cl(-)Secretion in Calu-3 Airway Epithelial Cells.Am J.Physiol 277(4 Pt 1):L700-8.Oct 1999.
Collins A.F.,Pearson H.A.,Giardina P.,McDonagh KT.,Brusilow SW.,Dover G.J.Oral Sodium Phenylbutyrate Therapy inHomozygous b Thalassemia:A Clinical Trial.Blood.85:43-49.1995
Dover D.,Brusilow S.,Samid D.Increased Fetal Hemoglobinin Patients Receiving Sodium 4-Phenylbutyrate.NewEng.J.Med.327:569-570,October 1,1992.
Dover G.J.,Brusilow,S.,Charache S.,Induction of FetalHemoglobin Production in Sub jects with Sickle Cell Anemia by OralSodium Phenylbutyrate.Blood.184(1):339-43.July 1994
Brusilow S.Phenylacetylglutamine May Replace Urea as aVehicle for Waste Nitrogen Excretion.Ped.Research.29(2):147-150.1991.
Brusilow S.,Danney M.,Waber L.,Batshaw M.,et al.Treatmentof Episodic Hyperammonemia in Children with Inborn Errors of UreaSynthesis.New Eng.J.Med.310:1630-34.June 1984.
Finkelstein J.E.,Hauser E.R.,Leonard C.O.,Brusilow S.W.Late-onset Omithine Transcarbamylase Deficiency in MalePatients.J Ped.117(6):897-902.1990.
Maestri N.,Hauser E.,Bartholomew D.,Brusilow S.ProspectiveTreatment of Urea Cycle Disorders.J Ped.119(6):923-928.1991.
Redonnet-Vernhet I.,Rouanet F.,Pedespan JM,Hocke,C.,Parrot F.,A Successful Pregnancy in a Heterozygote for OTCDeficiency Treated with Sodium Phenylbutyrate.Neurology.54(4):1008.Feb 2000.
Rowe P.,Newman S.,Brusilow S.Natural History of SymptomaticPartial Omithine Transcarbamylase Deficiency.NewEng.J.Med.314:541-547.1986.
Claims (17)
2.根据权利要求1的方法,其中所述碱为氢氧化钠。
3.根据权利要求1的方法,其中所有的R都为氢。
4.权利要求1的方法,其中催化剂为路易斯酸。
5.权利要求4的方法,其中催化剂为氯化铝、氯化锌、氯化铁、氯化亚锡、三溴化硼、三氟化硼或硫酸。
6.权利要求5的方法,其中催化剂为氯化铝。
7.权利要求6的方法,其中包含式II化合物和氯化铝的混合物在40℃至60℃一起搅拌10分钟,随后加入式III化合物。
8.权利要求7的方法,其中式III化合物与包含式II化合物和氯化铝的混合物在50℃至60℃一起搅拌90分钟,随后加入氢氧化钠。
9.权利要求3的方法,其中催化剂为路易斯酸。
10.权利要求9的方法,其中催化剂为氯化铝、氯化锌、氯化铁、氯化亚锡、三溴化硼、三氟化硼或硫酸。
11.权利要求10的方法,其中在苯与丁内酯反应之前将催化剂加入到苯中从而得到苯和催化剂的混合物。
12.权利要求11的方法,其中苯和催化剂的混合物在与丁内酯反应之前一起搅拌1分钟至15分钟。
13.权利要求12的方法,其中苯和催化剂的混合物在加入丁内酯之前在50℃至60℃下进行搅拌。
14.权利要求11的方法,其中丁内酯加入到苯和催化剂的混合物中,得到包含苯、催化剂和丁内酯的反应混合物。
15.权利要求14的方法,其中包含苯、催化剂和丁内酯的反应混合物搅拌30分钟至120分钟。
16.权利要求15的方法,其中包含苯、催化剂和丁内酯的反应混合物保持在50℃至60℃。
17.权利要求1的方法,进一步包括步骤:
c)过滤步骤b)的溶液以从水溶液中除去固体,
d)将步骤c)的溶液与有机溶剂接触以得到有机相和水相,
e)将水相与有机相中分离,
f)将酸加入到水相中以降低水相的pH值,加入量足以从水相中沉淀出产品,和
g)从水相中分离出产品。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/862,074 | 2001-05-21 | ||
US09/862,074 US6372938B1 (en) | 2001-05-21 | 2001-05-21 | Synthesis of 4-phenylbutyric acid |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1511133A CN1511133A (zh) | 2004-07-07 |
CN1266105C true CN1266105C (zh) | 2006-07-26 |
Family
ID=25337569
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB028102649A Expired - Fee Related CN1266105C (zh) | 2001-05-21 | 2002-05-02 | 4-苯丁酸的合成 |
Country Status (13)
Country | Link |
---|---|
US (1) | US6372938B1 (zh) |
EP (1) | EP1404638B1 (zh) |
JP (1) | JP4338401B2 (zh) |
KR (1) | KR100905139B1 (zh) |
CN (1) | CN1266105C (zh) |
AT (1) | ATE517857T1 (zh) |
CA (1) | CA2447803C (zh) |
HK (1) | HK1065996A1 (zh) |
HU (1) | HU229996B1 (zh) |
IL (2) | IL158914A0 (zh) |
PL (1) | PL201802B1 (zh) |
RU (1) | RU2297998C2 (zh) |
WO (1) | WO2002094756A1 (zh) |
Families Citing this family (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1291015A1 (en) * | 2001-09-10 | 2003-03-12 | Lunamed AG | Dosage forms having prolonged active ingredient release |
KR20050007570A (ko) * | 2002-06-03 | 2005-01-19 | 쇼와 덴코 가부시키가이샤 | 프리델-크래프트 반응에 의한 방향족 화합물의 제조방법 |
JP2008511611A (ja) * | 2004-08-30 | 2008-04-17 | ルナメツド・インコーポレーテツド | 治療用4−フェニル酪酸制御放出製剤 |
US20070004805A1 (en) * | 2005-07-01 | 2007-01-04 | Navinta Llc | Process for preparation of liquid dosage form containing sodium 4-phenylbutyrate |
US7968604B2 (en) * | 2005-09-23 | 2011-06-28 | Jeong-Woo Cho | Pharmaceutical composition for prevention and treatment of drug or alcohol addiction or bipolar disorder using sodium phenylbutyrate |
EP2555619A2 (de) * | 2010-04-06 | 2013-02-13 | Bayer Intellectual Property GmbH | Verwendung der 4-phenylbuttersäure und/oder ihrer salze zur steigerung der stresstoleranz in pflanzen |
KR101374241B1 (ko) * | 2010-11-17 | 2014-03-14 | 전북대학교병원 | 페닐부틸산(4-phenylbutyric acid)또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는, 천식 치료용 약학적 조성물 |
EP2599477A1 (en) | 2011-11-30 | 2013-06-05 | Lunamed AG | 4-Phenylbutyric acid sustained release formulation |
FR2993141B1 (fr) | 2012-07-11 | 2014-11-28 | Inst Rech Developpement Ird | Utilisation de l'acide 4-phenylbutyrique pour ameliorer la tolerance des plantes aux bioagresseurs |
CN103304403B (zh) * | 2013-05-24 | 2015-04-22 | 苏州诚和医药化学有限公司 | 一种4-苯-1-丁酸的合成方法 |
CN103304402B (zh) * | 2013-05-24 | 2015-04-22 | 苏州诚和医药化学有限公司 | 一种制备4-苯-1-丁酸的方法 |
US9914692B2 (en) * | 2016-05-25 | 2018-03-13 | Horizon Therapeutics, Llc | Procedure for the preparation of 4-phenyl butyrate and uses thereof |
CN106117045A (zh) * | 2016-06-22 | 2016-11-16 | 北京阳光诺和药物研究有限公司 | 一种苯基丁酸的纯化方法 |
CN108530290A (zh) * | 2018-06-04 | 2018-09-14 | 福州华博立乐新材料科技有限公司 | 一种4-苯基-1-丁酸的合成方法 |
CN110317132B (zh) * | 2019-07-26 | 2021-09-10 | 南京工业大学 | 一种苯丁酸钠的制备方法 |
FR3110336B1 (fr) | 2020-05-20 | 2022-12-23 | Inst Des Sciences Et Industries Du Vivant Et De Lenvir | Utilisation de l’Acide 4-phénylbutyrique et/ou de l’Acide 3-phénylbutyrique et/ou de l’Acide 2-phénylbutyrique pour la Prévention et le Traitement des Maladies Cryptogamiques |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6037376A (en) | 1991-10-21 | 2000-03-14 | The United States Of America As Represented By The Department Of Health And Human Services | Methods for therapy of cancer |
-
2001
- 2001-05-21 US US09/862,074 patent/US6372938B1/en not_active Expired - Lifetime
-
2002
- 2002-05-02 PL PL364646A patent/PL201802B1/pl unknown
- 2002-05-02 RU RU2003136765/04A patent/RU2297998C2/ru active
- 2002-05-02 AT AT02729112T patent/ATE517857T1/de not_active IP Right Cessation
- 2002-05-02 CN CNB028102649A patent/CN1266105C/zh not_active Expired - Fee Related
- 2002-05-02 HU HU0400053A patent/HU229996B1/hu not_active IP Right Cessation
- 2002-05-02 CA CA002447803A patent/CA2447803C/en not_active Expired - Lifetime
- 2002-05-02 WO PCT/US2002/013946 patent/WO2002094756A1/en active Application Filing
- 2002-05-02 IL IL15891402A patent/IL158914A0/xx unknown
- 2002-05-02 KR KR1020037014983A patent/KR100905139B1/ko active IP Right Grant
- 2002-05-02 EP EP02729112A patent/EP1404638B1/en not_active Expired - Lifetime
- 2002-05-02 JP JP2002591431A patent/JP4338401B2/ja not_active Expired - Fee Related
-
2003
- 2003-11-17 IL IL158914A patent/IL158914A/en active IP Right Grant
-
2004
- 2004-11-12 HK HK04108960A patent/HK1065996A1/xx not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
IL158914A (en) | 2010-04-29 |
HUP0400053A2 (hu) | 2004-04-28 |
JP2004527577A (ja) | 2004-09-09 |
US6372938B1 (en) | 2002-04-16 |
JP4338401B2 (ja) | 2009-10-07 |
EP1404638A1 (en) | 2004-04-07 |
EP1404638B1 (en) | 2011-07-27 |
HK1065996A1 (en) | 2005-03-11 |
IL158914A0 (en) | 2004-05-12 |
ATE517857T1 (de) | 2011-08-15 |
CN1511133A (zh) | 2004-07-07 |
HUP0400053A3 (en) | 2006-01-30 |
CA2447803A1 (en) | 2002-11-28 |
WO2002094756A1 (en) | 2002-11-28 |
CA2447803C (en) | 2009-04-07 |
PL364646A1 (en) | 2004-12-13 |
KR20040025679A (ko) | 2004-03-24 |
RU2003136765A (ru) | 2005-04-10 |
PL201802B1 (pl) | 2009-05-29 |
RU2297998C2 (ru) | 2007-04-27 |
HU229996B1 (hu) | 2015-04-28 |
KR100905139B1 (ko) | 2009-06-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1266105C (zh) | 4-苯丁酸的合成 | |
CN1128805C (zh) | 氯吡格雷硫酸氢盐的多晶型物及其制备方法和药物组合物 | |
CN1040746C (zh) | 维生素d类似物的新晶形 | |
FR2665453A1 (fr) | Polylactides purifies, procede pour leur preparation et compositions pharmaceutiques les contenant. | |
CN1747934A (zh) | 匹伐他汀钙的晶形 | |
CN1021228C (zh) | 改进的万古霉素沉淀法 | |
CN1213665A (zh) | 药用级泥炭黄腐植酸钠的制备方法 | |
CN1680374A (zh) | 含哌嗪环化合物的新型合成和结晶方法 | |
CN1202067C (zh) | 药用级枸橼酸铁的制备方法 | |
CN1275052A (zh) | 取代4-苯基-4-氰基环乙烷羧酸的制备方法 | |
CN1198798C (zh) | 用于制备α-(2,4-二磺基苯基)-N-叔丁基硝酮及其可药用的盐的新方法 | |
JPH07309862A (ja) | ラクチドの製造方法 | |
CN1325379A (zh) | L-dopa乙酯的制备方法 | |
JP2003502422A (ja) | パロキセチンおよび構造上関連する化合物の製法 | |
JP2006306809A (ja) | S−(−)−6−ヒドロキシ−2,5,7,8−テトラメチルクロマン−2−カルボン酸及びその製造方法 | |
CN1155553C (zh) | 2-氟-α-甲基-[1,1’-二苯基]-4-乙酸的对映体的制备方法 | |
CN1566080A (zh) | Dl-苯丙氨酸的拆分 | |
CN1088600C (zh) | 布洛芬-β-环糊精配合物的用途 | |
CN1704429A (zh) | 异甘草酸有机胺盐及其制备方法和用途 | |
CN1231489C (zh) | 木酚素化合物的胺盐 | |
CN1187307C (zh) | 一种从(S)-(+)-2-氟-α-甲基-[1,1'-二苯基]-4-乙酸的拆分母液制备(R)-(-)-2-氟-α-甲基-[1,1'-二苯基]-4-乙酸的方法 | |
CN1122802A (zh) | 古龙酸钠定量地转化制取抗坏血酸的方法 | |
CN1133633C (zh) | 西酞普兰的制备方法 | |
WO1988003023A1 (en) | Drug composition for treating liver diseases and process for its preparation | |
CN1906175A (zh) | 罗苏伐他汀的结晶铵盐 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1065996 Country of ref document: HK |
|
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: GR Ref document number: 1065996 Country of ref document: HK |
|
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20060726 Termination date: 20210502 |
|
CF01 | Termination of patent right due to non-payment of annual fee |