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WO1999007657A1 - Efficient synthesis of cyclopropylacetylene - Google Patents

Efficient synthesis of cyclopropylacetylene Download PDF

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Publication number
WO1999007657A1
WO1999007657A1 PCT/US1998/015957 US9815957W WO9907657A1 WO 1999007657 A1 WO1999007657 A1 WO 1999007657A1 US 9815957 W US9815957 W US 9815957W WO 9907657 A1 WO9907657 A1 WO 9907657A1
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Prior art keywords
formula
compound
represented
alkyl
base
Prior art date
Application number
PCT/US1998/015957
Other languages
French (fr)
Inventor
Sandor Karady
Benjamin Marcune
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Merck & Co., Inc.
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Priority claimed from GBGB9800464.1A external-priority patent/GB9800464D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU86049/98A priority Critical patent/AU738790B2/en
Priority to CA002298835A priority patent/CA2298835A1/en
Priority to EP98937309A priority patent/EP1001919A4/en
Priority to JP2000507195A priority patent/JP2001513518A/en
Publication of WO1999007657A1 publication Critical patent/WO1999007657A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C13/00—Cyclic hydrocarbons containing rings other than, or in addition to, six-membered aromatic rings
    • C07C13/02—Monocyclic hydrocarbons or acyclic hydrocarbon derivatives thereof
    • C07C13/04—Monocyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • a key step in the synthesis of the reverse transcriptase inhibitor, (-)-6-chloro-4-cyclopropylenthynyl-4-triflouromethyl- 1 ,4- dihydro-2H-3,l-benzoxazin-2-one, also known as DMP-266, is the chiral addition to the 2-flouromethylcarbonyl-4-choloroanaline using cyclopropyl acetylene as a nucleophile, a chiral additive, a non-chiral additive, and an organic.
  • the instant invention discloses a more efficient process for the synthesis of this important substrate.
  • the present invention relates to a process for the preparation of cyclopropyl acetylene (CPA), represented by formula I:
  • X is H, halo, CF 3 , or C-_ 6 alkyl
  • each R is independently a C,_ 6 alkyl and X is described above;
  • the instant invention relates to a process for the preparation of cyclopropyl acetylene (CPA), represented by formula I:
  • X is H, halo, CF 3 , or C-_ 6 alkyl
  • the base employed is an alkyl lithium such as phenyl lithium, Butyl lithium (BuLi) or a potassium alkyl such potassium methyl and the like , preferably BuLi and the silylating agent employed is selected from the group consisting of trialkylsilylchlorides, triakylsilyliodides and triflates such as trimethylsilylchloride, triethylsilylchloride, t-butyldimethylsilyl chloride, t-butyldiphenylsilylchloride, trimethylsilyltriflate, t- butyldimethylsilyltriflate, triethylsilyltriflate, triethylsilyliodide and the like, preferably trimethylsilylchloride (TMSC1).
  • TMSC1 trimethylsilylchloride
  • the solution of thioanisole consisting of thioanisole and a protic solvent such as tetrahydrofuran (THF), is cooled to a temperature of about -100°C to about -60°C, preferably - 95°C to about -70°C before contact with the strong base.
  • the solution is warmed to a temperature of about -5°C to about 5°C, preferably about -2°C to about 1°C for approximately 10 minutes to about one hour and then cooled to a temperature of about -100°C to about -60°C preferably - 95°C to about -70°C before contact with the silylating agent.
  • the mixture is warmed to a temperature of about - 5°C to about 5°C, preferably about -2°C to about 1°C for approximately 10 minutes to about one hour.
  • the base employed is an alkyl lithium such as phenyl lithium, Butyl lithium (BuLi) or a potassium alkyl such potassium methyl and the like , preferably BuLi.
  • the solution of Compound III is cooled to a temperature of about - 100°C to about -60°C, preferably - 95°C to about -70°C before contact with compound IV.
  • Compound V and VI are then reacted in the presence of potassium diaminopropane (KAPA) to yield the desired product, cyclopropyl acetylene (CPA).
  • KAPA potassium diaminopropane
  • alkyl relates to lower alkyls such as methyl, ethyl, isopropyl, butyl, propyl and the like.
  • halo relates to fluoro, chloro, iodo and bromo.
  • CPA can be isolated, after aqueous quench of the reaction, by extraction into an organic solvent, such a s hexane or toluene.
  • CPA can be isolated and purified by distillation.
  • KAPA may be generated from KH and diamino propane by methods known in the art.
  • Compound IV is cyclopropyl carboxaldehyde.
  • the present invention is embodied by the following non- limiting example.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

An efficient and facile process for the preparation of cyclopropylacetylene from thioanisole and cyclopropyl substituted ketones or aldehydes is disclosed

Description

TITLE OF THE INVENTION
EFFICIENT SYNTHESIS OF CYCLOPROPYLACETYLENE
BACKGROUND OF THE INVENTION A key step in the synthesis of the reverse transcriptase inhibitor, (-)-6-chloro-4-cyclopropylenthynyl-4-triflouromethyl- 1 ,4- dihydro-2H-3,l-benzoxazin-2-one, also known as DMP-266, is the chiral addition to the 2-flouromethylcarbonyl-4-choloroanaline using cyclopropyl acetylene as a nucleophile, a chiral additive, a non-chiral additive, and an organic.
The syntheses of DMP-266 and structurally similar reverse transcriptase inhibitors are disclosed in US Patent 5,519,021, and the corresponding PCT International Patent Application WO 95/20389, which published on August 3, 1995. Additionally, the asymmetric synthesis of an enantiomeric benzoxazinone by a highly enantioselective acetylide addition and cyclization sequence has been described by Thompson, et al, Tetrahedron Letters 7995, 36, 8937-8940, as well as the PCT publication, WO 96/37457, which published on November 28, 1996. Additionally, several applications have been filed which disclose various aspects of the synthesis of (-)-6-chloro-4-cyclopropyl- ethynyl-4-triflouromethyl- 1 ,4-dihy dro-2H-3 , 1 -benzoxazin-2-one, including: 1) a process for the preparation of cyclopropylacetylene by cyclizing 5-halo-l-pentyne published on August 1, 1996 in PCT Publication No. WO 96/22955; 2) a process for making the chiral alcohol, U.S.S.N. 60/035,462, filed 14 January 1997; 3) the chiral additive, U.S.S.N. 60/034,926, filed 10 January 1997; 4) the cyclization reaction, U.S.S.N. 60/037,059, filed 12 February 1997; 5) the anti- solvent crystallization procedure, Case No. 19905PV2 (US Serial No. unknown), filed May 23, 1997.
Several methods have been described in published literature for preparation of cyclopropylacetylene. C.E. Hudson and N.L. Bauld, J.A.C.S. 94:4, p.1158 (1972); J. Salaun, J.O.C. 41:7 p.1237 (1976); and W. Schoberth and M. Hanack, Synthesis (1972). p.703 disclose methods for the preparation of cyclopropylacetylene by dehydrohalogenating 1- cyclopropyl-l,l-dichloroethane. Miltzer, H.C. et ah, Synthesis, 998 (1993) disclose a method for preparation of cyclopropylalkenes by halogenating an enolether, reacting the alkyl 1,2-dihaloether with propargyl magnesium bromide, and cyclizing to give a 2-alkoxy -1- ethynylcyclopropane. F.A. Carey and A. S. Court, J. Org. Chem., Vol. 37, No.12, (1972) p. 1926 disclose the use of a modified Wittig-Horner olefin synthesis for organcic transformations; D. J. Peterson, J. Org. Chem., Vol. 20C, No. 33, (1968) p. 780 describes the application of olfenation to make vinyl sulfides and H. Takeshita and T. Hatsui, J. Org. Chem., Vol. 43, No. 15, (1978) p. 3083 disclose the use of potassium 3- aminopropylamide in base-catalyzed prototropic reactions.
As illustrated by the Scheme below, Schoberth, et al. , describes a method which resulted in about a 42% yield of the cyclopropylacetylene.
Figure imgf000004_0001
The instant invention discloses a more efficient process for the synthesis of this important substrate.
SUMMARY OF THE INVENTION
The present invention relates to a process for the preparation of cyclopropyl acetylene (CPA), represented by formula I:
Figure imgf000004_0002
which comprises reacting thioanisole represented by formula II:
Figure imgf000005_0001
II
wherein X is H, halo, CF3, or C-_6 alkyl;
in the presence of a base and a silylating agent, to a compound represented by formula III:
Figure imgf000005_0002
III
wherein each R is independently a C,_6 alkyl and X is described above;
reacting a compound of formula III with a compound of formula IV:
Figure imgf000005_0003
IV
in the presence of a base to yield vinyl thioethers, represented by formula V and VI:
Figure imgf000006_0001
v VI
reacting a compound of formula V and VI in the presence of potassium diaminopropane (KAPA) to yield cyclopropyl acetylene.
This process is a more facile and efficient alternative to known synthetic pathways insofar as the entire scheme can be carried out in a single eaction vessel by sequential addition of the required reagents.
DETAILED DESCRIPTION OF THE INVENTION
The instant invention relates to a process for the preparation of cyclopropyl acetylene (CPA), represented by formula I:
Figure imgf000007_0001
First, a solution of thioanisole, represented by formula II:
Figure imgf000007_0002
II
wherein X is H, halo, CF3, or C-_6 alkyl;
is reacted in the presence of a base and a silylating agent to yield a compound represented by formula III:
Figure imgf000007_0003
III wherein X and R are described above, For purposes of this invention, the base employed is an alkyl lithium such as phenyl lithium, Butyl lithium (BuLi) or a potassium alkyl such potassium methyl and the like , preferably BuLi and the silylating agent employed is selected from the group consisting of trialkylsilylchlorides, triakylsilyliodides and triflates such as trimethylsilylchloride, triethylsilylchloride, t-butyldimethylsilyl chloride, t-butyldiphenylsilylchloride, trimethylsilyltriflate, t- butyldimethylsilyltriflate, triethylsilyltriflate, triethylsilyliodide and the like, preferably trimethylsilylchloride (TMSC1). The solution of thioanisole, consisting of thioanisole and a protic solvent such as tetrahydrofuran (THF), is cooled to a temperature of about -100°C to about -60°C, preferably - 95°C to about -70°C before contact with the strong base. Upon contact with the base the solution is warmed to a temperature of about -5°C to about 5°C, preferably about -2°C to about 1°C for approximately 10 minutes to about one hour and then cooled to a temperature of about -100°C to about -60°C preferably - 95°C to about -70°C before contact with the silylating agent. After addition of the silyating agent the mixture is warmed to a temperature of about - 5°C to about 5°C, preferably about -2°C to about 1°C for approximately 10 minutes to about one hour.
Next, Compound III is reacted with a compound of formula IV:
Figure imgf000008_0001
IV
in the presence of a base to yield vinyl thioethers, represented by formula V and VI:
Figure imgf000009_0001
For purposes of this invention, the base employed is an alkyl lithium such as phenyl lithium, Butyl lithium (BuLi) or a potassium alkyl such potassium methyl and the like , preferably BuLi. The solution of Compound III is cooled to a temperature of about - 100°C to about -60°C, preferably - 95°C to about -70°C before contact with compound IV. Finally, Compound V and VI are then reacted in the presence of potassium diaminopropane (KAPA) to yield the desired product, cyclopropyl acetylene (CPA).
The term alkyl relates to lower alkyls such as methyl, ethyl, isopropyl, butyl, propyl and the like. The term halo relates to fluoro, chloro, iodo and bromo.
CPA can be isolated, after aqueous quench of the reaction, by extraction into an organic solvent, such a s hexane or toluene. Alternatively, CPA can be isolated and purified by distillation.
The reagents used in this process are either commercially available or may be prepared by synthetic methods commonly known in the art. KAPA may be generated from KH and diamino propane by methods known in the art.
Some of the intermediate compounds synthesized in the present invention occur as geometric isomers. The processes of synthesizing all such isomers are included in the present invention.
In another preferred aspect of this invention, Compound IV is cyclopropyl carboxaldehyde. The present invention is embodied by the following non- limiting example.
EXAMPLE
Reaction Scheme
Figure imgf000010_0001
Procedure
Step 1
A solution of thioanisole (4.7 g, 1.05 mmoles) in 19 ml of THF was cooled to -78°C and a hexane solution of butyl lithium ( 14.5 ml 2.05 mmoles) was added and the solution was warmed to 0°C for 30 minutes to complete anion formation. After this the solution was cooled to -78C and trimethylsilyl chloride (4g, 1.03 mmoles) was added, followed by warming to 0°C for 30 minutes. Step 2
The resulting mixture was cooled again to -78°C before another portion of butyl lithium (14.4 ml, 2.05 mmole) was added . After warming and aging at 0°C for 30 minutes, cyclopropyl carboxaldehyde(2.5 g, 1.0 mmole) was added at -78°C. The mixture was stirred overnight at room temperature and then quenched with 100ml of water. The organic product was extracted with 40 ml of hexane followed by evaporation. The NMR spectrum indicated that a mixture of E and Z thiovinyl ethers 3 and 4 were produced. Alternatively, commercially available TMS thioanisole may be employed and the reaction initiated at Step 2 according to the following procedure:
A solution of (phenylthiomethyl)trimethylsilane 2ml (10 mmole) in THF(5ml) was cooled to -78°C and a hexane solution of butyllithium (4.5 ml ,2.25 mmole) was added. The solution was allowed to warm to room temperature, then it was cooled again to -78°C and cyclopropane carboxaldehyde (0.75 ml, 10 mmole) was added dropwise. The reaction mixture was kept at -78°C for an additional two hours and then it was allowed to warm to room temperature. The mixture was extracted with water and the solvent was removed to give an oil. The NMR spectrum of this mixture was identical with that of the product obtained for synthesized TMS thioanisole, as described above. This mixture was used without purification for the next step.
Step 3
A solution of the mixture of the vinyl sulfides 3 and 4, from the previous reactions, (176 mg, 0.85 mm) in diaminopropane (lml) was cooled with ice and a solution of KAPA (potassium diaminopropane, 2 mmoles) in 2ml of diaminopropane was added. After this the solution was allowed to stir at room temperature for 18 hr. A GC assay indicated that 41 mg cyclopropyl acetylene was produced in 62% yield.

Claims

WHAT IS CLAIMED IS:
1. A process for the preparation of cyclopropyl acetylene (CPA), represented by formula I:
Figure imgf000012_0001
which comprises reacting a compound represented by formula II:
Figure imgf000012_0002
II
wherein X is H, halo, CF3, or C-.6 alkyl;
in the presence of a base and a silylating agent, to a compound represented by formula III:
Figure imgf000012_0003
wherein each R is independently a C._6 alkyl and X is described above; reacting a compound of formula III with a compound of formula IV:
Figure imgf000013_0001
IV
in the presence of a base to yield a vinyl thioether, represented by formula V and VI:
Figure imgf000013_0002
V VI
reacting a compound of formula V and VI in the presence of potassium diaminopropane (KAPA) to yield cyclopropyl acetylene.
2. The process of Claim 1 wherein the base employed is an alkyl lithium such as phenyl lithium, Butyl lithium (BuLi) or a potassium alkyl such potassium methyl and the compound of formula II - is reacted with the base at a temperature of about -100┬░C to about - 60┬░C.
3. The process according to claim 2 wherein the temperature is about -95┬░C to about -70┬░C and the base is BuLi.
4. The process of Claim 1 wherein the silylating agent employed are trialkylsilylchlorides, triakylsilyliodides and triflates.
5. The process of Claim 4 wherein the silylating agents are trimethylsilylchloride, triethylsilylchloride, t-butyldimethylsilyl chloride, t-butyldiphenylsilylchloride, trimethylsilyltriflate, t- butyldimethylsilyltriflate, triethylsilyltriflate, and triethylsilyliodide.
6. The process of Claim 5 wherein the silylating agent is trimethylsilylchloride.
7. The process of Claim 1 wherein Compound IV is cyclopropyl carboxaldehyde.
8. A process for the preparation of cyclopropyl acetylene (CPA), represented by formula I:
Figure imgf000014_0001
which comprises reacting a compound of formula II:
Figure imgf000014_0002
II
wherein X is H, halo, CF3, or C-.6 alkyl; in the presence of BuLi and TMSC1, to a compound represented by formula III:
Figure imgf000015_0001
wherein each R is independently a C-_6 alkyl and X is described above;
reacting a compound of formula III with a cyclopropyl carboxaldehyde, represented by formula IV:
O ziΛ H
IV
in the presence of BuLi to yield vinyl thioethers, represented by formula V and VI:
Figure imgf000015_0002
V VI
reacting a compound of formula V and VI in the presence of potassium diaminopropane (KAPA) to yield cyclopropyl acetylene.
PCT/US1998/015957 1997-08-06 1998-08-03 Efficient synthesis of cyclopropylacetylene WO1999007657A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU86049/98A AU738790B2 (en) 1997-08-06 1998-08-03 Efficient synthesis of cyclopropylacetylene
CA002298835A CA2298835A1 (en) 1997-08-06 1998-08-03 Efficient synthesis of cyclopropylacetylene
EP98937309A EP1001919A4 (en) 1997-08-06 1998-08-03 Efficient synthesis of cyclopropylacetylene
JP2000507195A JP2001513518A (en) 1997-08-06 1998-08-03 Efficient synthesis of cyclopropylacetylene

Applications Claiming Priority (4)

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US5486097P 1997-08-06 1997-08-06
US60/054,860 1997-08-06
GBGB9800464.1A GB9800464D0 (en) 1998-01-09 1998-01-09 Efficient synthesis of cycloproplacetylene
GB9800464.1 1998-01-09

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5519021A (en) * 1992-08-07 1996-05-21 Merck & Co., Inc. Benzoxazinones as inhibitors of HIV reverse transcriptase
US5633405A (en) * 1995-05-25 1997-05-27 Merck & Co., Inc. Asymmetric synthesis of (-)-6-chloro-4-cyclopropyl-ethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxanzin-2-one
US5663467A (en) * 1995-01-23 1997-09-02 Merck & Co., Inc. Synthesis of cyclopropylacetylene

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5519021A (en) * 1992-08-07 1996-05-21 Merck & Co., Inc. Benzoxazinones as inhibitors of HIV reverse transcriptase
US5663169A (en) * 1992-08-07 1997-09-02 Merck & Co., Inc. Benzoxazinones as inhibitors of HIV reverse transcriptase
US5665720A (en) * 1992-08-07 1997-09-09 Merck & Co., Inc. Benzoxazinones as inhibitors of HIV reverse transcriptase
US5811423A (en) * 1992-08-07 1998-09-22 Merck & Co., Inc. Benzoxazinones as inhibitors of HIV reverse transcriptase
US5663467A (en) * 1995-01-23 1997-09-02 Merck & Co., Inc. Synthesis of cyclopropylacetylene
US5633405A (en) * 1995-05-25 1997-05-27 Merck & Co., Inc. Asymmetric synthesis of (-)-6-chloro-4-cyclopropyl-ethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxanzin-2-one
US5698741A (en) * 1995-05-25 1997-12-16 Merck & Co. Inc. Asymmetric synthesis of (-)6-chloro-4-cyclopropyl-ethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP1001919A4 *

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EP1001919A4 (en) 2000-10-11
EP1001919A1 (en) 2000-05-24
AU738790B2 (en) 2001-09-27
JP2001513518A (en) 2001-09-04
AU8604998A (en) 1999-03-01
CA2298835A1 (en) 1999-02-18

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